Total synthesis of myriaporones

ABSTRACT

Compounds of the general formula (I) or a pharmaceutically acceptable salt, derivative, prodrug or stereoisomer therefor are provided: wherein the substituent groups defined by R are each independently selected from the group consisting of H, SiR′ 3 , SOR′, SO 2 X, C(═O)R′, C(═O)OR′, C(═O)NR′, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, aryl, heteroaryl or aralkyl; the group R′ is selected from substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, aminoalkyl, aryl, aralkyl and heterocyclic groups; and the group R″ is selected from the group consisting of H, OH, OR′, OCOR′, SH, SR′, SOR′, SO 2 R′, NO 2 , NH 2 , NHR′, N(R′) 2 , NHCOR′, N(COR′) 2 , NHSO 2 R′, CN, halogen, C(═O)H, C(═O)R′, CO 2 H, CO 2 R′, CH 2 OR, substituted or unsubstituted alkyl, substituted or unsubstituted haloalkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkylidene, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl and substituted or unsubstituted heteroaromatic; with the proviso that the compound is not compound 1, 3 or 4 of U.S. Pat. No. 5,514,708. The compounds have antitumour activity. A synthetic route is also provided.

The present invention relates to new myriaporones analogues and theiruse for the treatment of cancer. The present invention also relates to atotal synthesis of myriaporones and derivatives.

BACKGROUND OF THE INVENTION

Myriaporones are a new class of marine polyketide-derived isolated fromthe bryozoan Myriapora truncata.

Myriaporones are disclosed to have antitumor activity. The completestructure for these related compounds was given by K. L. Rinehart etal., J. Nat. Prod. 1995, 58, 344 and U.S. Pat. No. 5,514,708.Myriaporones 3 and 4 described there are in an equilibrium mixturebetween the free hydroxy ketone and the hemiketal as indicated in thefigure above.

There have been several unsuccessful attempts at the synthesis ofmyriaporones, see for example Taylor, R. E.; Ciavarri, J. C.; Hearn, B.R. “A Divergent Approach the Myriaporones and Tedanolide:Enantioselective Preparation of the Common Intermediate” TetrahedronLett. 1998, 39, 9361; Taylor et al., Org. Lett. 2002, 4, 2853, availableon the Web 02 Aug. 2002.

In view of their interesting biological properties there is a need toprovide an efficient, stereocontrolled total synthesis of myriaporonesand related compounds.

SUMMARY OF THE INVENTION

In a first aspect, the present invention is directed to compounds ofgeneral formula I or a pharmaceutically acceptable salt, derivative,prodrug or stereoisomer thereof

wherein the substituent groups defined by R are each independentlyselected from the group consisting of H, SiR′₃, SOR′, SO₂R′, C(═O)R′,C(═O)OR′, C(═O)NR′, substituted or unsubstituted alkyl, substituted orunsubstituted alkenyl, substituted or unsubstituted alkynyl, aryl,heteroaryl or aralkyl;

the group R′ is selected from substituted or unsubstituted alkyl,substituted or unsubstituted alkenyl, substituted or unsubstitutedalkynyl, aminoalkyl, aryl, aralkyl and heterocyclic groups; and

the group R″ is selected from the group consisting of H, OH, OR′, OCOR′,SH, SR′, SOR′, SO₂R′, NO₂, NH₂, NHR′, N(R′)₂, NHCOR′, N(COR′)₂, NHSO₂R′,CN, halogen, C(═O)H, C(═O)R′, CO₂H, CO₂R′, CH₂OR, substituted orunsubstituted alkyl, substituted or unsubstituted haloalkyl, substitutedor unsubstituted alkenyl, substituted or unsubstituted alkylidene,substituted or unsubstituted alkynyl, substituted or unsubstituted aryl,substituted or unsubstituted aralkyl and substituted or unsubstitutedheteroaromatic;

with the proviso that the compound is not compound 1, 3 or 4 of U.S.Pat. No. 5,514,708.

Compound 1 of U.S. Pat. No. 5,514,708 corresponds to formula 1 shownabove in the description of the prior art.

According to our findings, the natural compounds 3 and 4 of U.S. Pat.No. 5,514,708 correspond to compounds 4a and 3a as described in theexamples below.

When R″ is CH₂OH compounds of formula I may exist as a mixture of theketone isomer and the hemiketal isomer (5),

wherein the substituent groups defined by R are as defined above.

In particular, we prefer that at least one of the R substituents is nothydrogen. We have found that these compounds show improved cytotoxicity.

Myriaporones are obtained from natural sources. Another objective of thepresent invention is to provide a synthetic route to producemyriaporones and derivatives. Therefore, the present invention isdirected to the synthesis of the compounds of formula I as definedabove, including those where all R groups are H, and to intermediatesused in the synthetic process.

According to the present invention, a process of this invention involvesremoving a protecting group from a compound of formula 5a wherein atleast one group R is a protecting group to give the correspondingcompound of formula 5b where the said at least one group R is hydrogen.This synthetic route can be applied to new and known myriaporones.

Another embodiment of the present invention is a pharmaceuticalcomposition comprising a compound of formula I or a pharmaceuticallyacceptable salt, derivative, prodrug or stereoisomer thereof or anintermediate of their synthesis and a pharmaceutically acceptablecarrier.

Another embodiment of the present invention is the use of compounds offormula I or pharmaceutically acceptable salts, derivatives, prodrugs orstereoisomers thereof as antitumor agents.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to compounds of formula I as definedabove.

In these compounds the substituents can be selected in accordance withthe following guidance:

Alkyl groups preferably have from 1 to 12 carbon atoms. One morepreferred class of alkyl groups has 1 to about 8 carbon atoms, stillmore preferably 1 to about 6 carbon atoms, and most preferably 1, 2, 3or 4 carbon atoms. Methyl, ethyl and propyl including isopropyl areparticularly preferred alkyl groups in the compounds of the presentinvention. As used herein, the term′ alkyl, unless otherwise modified,refers to both cyclic and noncyclic groups, although cyclic groups willcomprise at least three carbon ring members.

Preferred alkenyl and alkynyl groups in the compounds of the presentinvention have one or more unsaturated linkages and from 2 to about 12carbon atoms, more preferably 2 to about 8 carbon atoms, still morepreferably 2 to about 6 carbon atoms, even more preferably 2, 3 or 4carbon atoms. The terms alkenyl and alkynyl as used herein refer to bothcyclic and noncyclic groups, although straight or branched noncyclicgroups are generally more preferred.

Alkylidene groups may be branched or unbranched and preferably have from1 to 12 cabon atoms. One more preferred class of alkylidene groups hasfrom 1 to about 8 carbon atoms, yet more preferably from 1 to about 6carbon atoms, and most preferably 1, 2, 3 or 4 carbon atoms.Methylidene, ethylidene and propylidene including isopropylidene areparticularly preferred alkylidene groups in the compounds of the presentinvention

Preferred alkylsulfinyl groups in the compounds of the present inventioninclude those groups having one or more sulfoxide (SO) groups and from 1to about 12 carbon atoms, more preferably from 1 to about 8 carbonatoms, and still more preferably 1 to about 6 carbon atoms.Alkylsulfinyl groups having 1, 2, 3 or 4 carbon atoms are particularlypreferred.

Preferred alkylsulfonyl groups in the compounds of the present inventioninclude those groups having one or more sulfonyl (SO₂) groups and from 1to about 12 carbon atoms, more preferably from 1 to about 8 carbonatoms, and still more preferably 1 to about 6 carbon atoms.Alkylsulfonyl groups having 1, 2, 3 or 4 carbon atoms are particularlypreferred.

Preferred aminoalkyl groups include those groups having one or moreprimary, secondary and/or tertiary amine groups, and from 1 to about 12carbon atoms, more preferably 1 to about 8 carbon atoms, still morepreferably 1 to about 6 carbon atoms, even more preferably 1, 2, 3 or 4carbon atoms. Secondary and tertiary amine groups are generally morepreferred than primary amine moieties.

Suitable heterocyclic groups include heteroaromatic and heteroalicyclicgroups. Suitable heteroaromatic groups in the compounds of the presentinvention contain one, two or three heteroatoms selected from N, O or Satoms and include, e.g., coumarinyl including 8-coumarinyl, quinolinylincluding 8-quinolinyl, pyridyl, pyrazinyl, pyrimidyl, furyl, pyrrolyl,thienyl, thiazolyl, oxazolyl, imidazolyl, indolyl, benzofuranyl andbenzothiazol. Suitable heteroalicyclic groups in the compounds of thepresent invention contain one, two or three heteroatoms selected from N,O or S atoms and include, e.g., tetrahydrofuranyl, tetrahydropyranyl,piperidinyl, morpholino and pyrrolindinyl groups.

Suitable aryl groups in the compounds of the present invention includesingle and multiple ring compounds, including multiple ring compoundsthat contain separate and/or fused aryl groups. Typical aryl groupscontain from 1 to 3 separated or fused rings and from 6 to about 18carbon ring atoms. Specifically preferred aryl groups includesubstituted or unsubstituted phenyl, naphthyl, biphenyl, phenanthryl,and anthracyl.

References herein to substituted groups in the compounds of the presentinvention refer to the specified moiety, typically alkyl or alkenyl,that may be substituted at one or more available positions by one ormore suitable groups, e.g., halogen such as fluoro, chloro, bromo andiodo; cyano; hydroxyl; nitro; azido; carboxamido; alkyl groups includingthose groups having 1 to about 12 carbon atoms, preferably from 1 toabout 6 carbon atoms and more preferably 1-3 carbon atoms; alkenyl andalkynyl groups including groups having one or more unsaturated linkagesand from 2 to about 12 carbon or from 2 to about 6 carbon atoms; alkoxygroups having those having one or more oxygen linkages and from 1 toabout 12 carbon atoms, preferably from 1 to about 6 carbon atoms;aryloxy such as phenoxy; alkylthio groups including those moietieshaving one or more thioether linkages and from 1 to about 12 carbonatoms, preferably from 1 to about 6 carbon atoms; alkylsulfinyl groupsincluding those moieties having one or more sulfinyl linkages and from 1to about 12 carbon atoms, preferably from 1 to about 6 carbon atoms;alkylsulfonyl groups including those moieties having one or moresulfonyl linkages and from 1 to about 12 carbon atoms, preferably from 1to about 6 carbon atoms; aminoalkyl groups such as groups having one ormore N atoms and from 1 to about 12 carbon atoms, preferably from 1 toabout 6 carbon atoms; aryl having 6 or more carbons, particularlyphenyl; aralkyl such as benzyl; heterocyclic groups includingheteroalicyclic and heteroaromatic groups, especially with 5 to 10 ringatoms of which I to 4 are heteroatoms, more preferably heterocyclicgroups with 5 or 6 ring atoms and 1 or 2 heteratoms or with 10 ringatoms and 1 to 3 heteroatoms.

Preferred R groups include alkyl, alkenyl and alkynyl that may besubstituted at one or more available positions by one or more suitablegroups, e.g., halogen such as fluoro, chloro, bromo and iodo, especiallyω-chloro or perfluoro; aminoalkyl groups such as groups having one ormore N atoms and from 1 to about 12 carbon atoms, preferably from 1 toabout 6 carbon atoms; aryl having 6 or more carbons, particularlyphenyl; aralkyl such as benzyl; heterocyclic groups includingheteroalicyclic and heteroaromatic groups, especially with 5 to 10 ringatoms of which 1 to 4 are heteroatoms, more preferably heterocyclicgroups with 5 or 6 ring atoms and 1 or 2 heteratoms or with 10 ringatoms and 1 to 3 heteroatoms, the heterocyclic groups optionally beingsubstituted with one or more of the substituents, especially amino suchas dimethylamino or with keto.

The term “pharmaceutically acceptable salts, derivatives, prodrugs”refers to any pharmaceutically acceptable salt, ester, solvate, hydrateor any other compound which, upon administration to the recipient iscapable of providing (directly or indirectly) a compound as describedherein. However, it will be appreciated that non-pharmaceuticallyacceptable salts also fall within the scope of the invention since thosemay be useful in the preparation of pharmaceutically acceptable salts.The preparation of salts, prodrugs and derivatives can be carried out bymethods known in the art.

For instance, pharmaceutically acceptable salts of compounds providedherein are synthesized from the parent compound which contains a basicor acidic moiety by conventional chemical methods. Generally, such saltsare, for example, prepared by reacting the free acid or base forms ofthese compounds with a stoichiometric amount of the appropriate base oracid in water or in an organic solvent or in a mixture of the two.Generally, nonaqueous media like ether, ethyl acetate, ethanol,isopropanol or acetonitrile are preferred. Examples of the acid additionsalts include mineral acid addition salts such as, for example,hydrochloride, hydrobromide, hydroiodide, sulphate, nitrate, phosphate,and organic acid addition salts such as, for example, acetate, maleate,fumarate, citrate, oxalate, succinate, tartrate, malate, mandelate,methanesulphonate and p-toluenesulphonate. Examples of the alkaliaddition salts include inorganic salts such as, for example, sodium,potassium, calcium and ammonium salts, and organic alkali salts such as,for example, ethylenediamine, ethanolamine, N,N-dialkylenethanolamine,triethanolamine and basic aminoacids salts.

The compounds of the invention may be in crystalline form either as freecompounds or as solvates (e.g. hydrates) and it is intended that bothforms are within the scope of the present invention. Methods ofsolvation are generally known within the art.

Any compound that is a prodrug of a compound of formula I is within thescope and spirit of the invention. The term “prodrug” is used in itsbroadest sense and encompasses those derivatives that are converted invivo to the compounds of the invention. Such derivatives would readilyoccur to those skilled in the art, and include, for example, compoundswhere a free hydroxy group is converted into an ester derivative.

The compounds of the present invention represented by the abovedescribed formula I may include enantiomers depending on their asymmetryor diastereoisomers. The single isomers and mixtures of the isomers fallwithin the scope of the present invention.

In one aspect, the present invention extends to compounds of formula Iwhich differ from the known myriaporones in respect of one or morepositions of stereochemistry. Thus, in this aspect, the compounds areisomers and isomeric derivatives.

The preferred stereochemistry of compounds of formula I is thefollowing:

When R″ is CH₂OH the preferred stereochemistry of compounds of formula 5is:

Particularly preferred are compounds having the followingstereochemistry:

We have found that these particular groups of compounds show improvedbiological properties.

In another preferred embodiment of the present invention, R″ is asubstituted or unsubstituted alkylidene.

In one preferred embodiment of the compounds of formula 5, at least oneof the R substituents is C(═O)R′. Particularly preferred is the compoundof formula 47:

In another embodiment of the compounds of formula I or of formula 5, atleast one of the R substituents is not hydrogen. Suitably, each groupthat is not hydrogen is a protecting group, which may be the same ordifferent.

Compounds of the following formula are preferred:

where R¹, R², R⁶ and R⁷ are hydroxy protecting groups.

Particularly preferred are compounds of formula 19:

where R¹, R², R⁶ and R⁷ are hydroxy protecting groups; and of formula30:

where R¹, R², R⁶ and R⁷ are hydroxy protecting groups.

Suitably, R¹, R², R⁶ and R⁷ are the same protecting group. They can bechosen from TBS (tBuMe₂Si—), TBDPS (tBuPh₂Si—), TES (Et₃Si—), MOM(CH₃OCH₂—), MEM (CH₃OCH₂CH₂CO—). Especially preferred is TBS (tBuMe₂Si—)or TBDPS (tBuPh₂Si—).

Also preferred are compounds of the following formula:

where R¹ is a hydroxy protecting group.

Particularly preferred are compounds of formula 20 and 31:

In the above compounds, R¹ is suitably TBS (tBuMe₂Si—).

The present invention also provides a process for synthesis of amyriaporone compound of formula 5:

which may exist as a mixture of the ketone isomer and the hemiketalisomer, or as one of the two isomeric forms;

wherein the substituent groups defined by R are each independentlyselected from the group consisting of H, SiR′₃, SOR′, SO₂R′, C(═O)R′,C(═O)OR′, C(═O)NR′, substituted or unsubstituted alkyl, substituted orunsubstituted alkenyl, substituted or unsubstituted alkynyl, aryl,heteroaryl or aralkyl, and wherein at least one group R is hydrogen;

and wherein the group R′ is selected from substituted or unsubstitutedalkyl, substituted or unsubstituted alkenyl, substituted orunsubstituted alkynyl, aminoalkyl, aryl, aralkyl and heterocyclicgroups;

which comprises removing a protecting group from an intermediatecompound of formula:

wherein the substituent groups defined by R are each independentlyselected from the group consisting of H, SiR′₃, SOR′, SO₂R′, C(═O)R′,C(═O)OR′, C(═O)NR′, substituted or unsubstituted alkyl, substituted orunsubstituted alkenyl, substituted or unsubstituted alkynyl, aryl,heteroaryl or aralkyl, and wherein the or each group R to becomehydrogen in the compound 5 is in the intermediate compound protectinggroup;

and wherein the group R′ is as defined.

Suitably, more than one group R in the intermediate compound is aprotecting group.

A process of this invention can comprise removing at least oneprotecting group from a compound of formula 19:

where R¹, R², R⁶ and R⁷ are hydroxy protecting groups.

A related process of this invention can comprise removing at least oneprotecting group from a compound of formula 30:

where R¹, R², R⁶ and R⁷ are hydroxy protecting groups.

Suitably R¹, R², R⁶ and R⁷ are the same protecting group and areremoved.

Another process of this invention comprises removing a protecting groupfrom a compound of formula 20:

where R¹ is a hydroxy protecting group.

A related process comprises removing a protecting group from a compoundof formula 31:

where R¹ is a hydroxy protecting group.

The invention further provides a process for synthesis of a myriaporonecompound of formula I:

wherein the substituent groups R and R″ are as defined above for theformula I; which comprises derivatisation of a compound of formula 5:

which may exist as a mixture of the ketone isomer and the hemiketalisomer, or as one of the two isomeric forms;

and wherein the substituent groups are as defined in claim 25.

The invention further provides compounds of the following formula

where R¹, R² and R⁴ are hydroxy protecting groups, and L is astereospecific leaving group which induces chirality.

Preferred are compounds of formula 10 and 22:

The invention also provides compounds of the following formula:

wherein R¹, R², R⁴and R⁶ are hydroxy protecting groups;

R⁵ is selected from the group consisting of H, SOR′, SO₂R′, C(═O)R′,C(═O)OR′, C(═O)NR′, substituted or unsubstituted alkyl, substituted orunsubstituted alkenyl, substituted or unsubstituted alkynyl, aryl,heteroaryl or aralkyl; and R′ has the same meaning as defined in claim1.

Preferred are compounds of formula 14 and 26:

The invention also provides a process for preparation of a compound offormula 14 which comprises chain extension of a compound of formula 13;a process for preparation of a compound of formula 26 which compriseschain extension of a compound of formula 25; a process for preparationof a compound of formula 19 which comprises chain extension of acompound of formula 18; and a process for preparation of a compound offormula 30 which comprises chain extension of a compound of formula 29.

The invention also provides compounds of the following formula:

wherein R¹, R² and R⁴ are hydroxy protecting groups.

Preferred are compounds of formula 11 and 23:

The invention also provides compounds of the following formula:

wherein R¹, R² and R⁴ are hydroxy protecting groups.

Compounds of formula 8 are preferred:

The compounds of the present invention can be synthetically preparedfrom the intermediate compound 6 described by W. R. Roush et al., OrgLett. 1999, 1, 95 or its stereoisomers.

A method of producing compounds of formula I is shown in the Scheme 1.

For the purpose of discussing this scheme, the carbons in eachrespective molecule are assigned with the appropriate number to theirfinal position at the end product of formula I, using the numberingsystem given previously for the known compound 3/4.

The scheme 1 involves:

-   -   protecting the compound 6 to give protected compound 7. This        protection is carried out with the related reagent of the        selected protecting group (such as TBSCl, TESOTf, MOMBr or        tBu₂Si(OTf)₂) in the conditions according to known procedures in        organic synthesis (for example: imidazole, DIPEA or 2,6-lutidine        in DMF or CH₂Cl₂), alternative protecting groups are also        contemplated,    -   converting the terminal vinyl group at carbons 6 and 7 to an        aldehyde in compound 8. This conversion is carried out by        ozonolysis of the vinyl group (for example with O₃, in CH₂Cl₂ at        −78° C.) or by formation of the corresponding dihydroxy        derivative (for example with NMO, OsO₄ in THF:H₂O) and the diol        is cleavaged (for example with NaIO₄ in THF:H₂O) to the        corresponding aldehyde,    -   reaction with an oxazolidinone 9 to give compound 10. The        oxazolidinone 9 is converted into the corresponding enolate (for        example with Bu₂BOTf and Et₃N in CH₂Cl₂ at −78° C.) and added to        8 at low temperature (−30° C.) to give 10. Other stereospecific        leaving groups which induce the desired chirality are also        contemplated within the scope of protection of the invention.    -   reduction of compound 10 to obtain a 17-hydroxymethyl sidechain        in the compound 11. This reduction is carried out with the        corresponding reagent (such as LiBH₄) in the conditions (for        example in THF:H₂O or CH₂Cl₂) according to known procedures in        organic synthesis, although other reducing agents are also        contemplated within the scope of protection of the invention.    -   further protection at the 17-hydroxy group to give compound 12.        This protection is carried out with the related reagent of the        selected protecting group (such as TBSCl, TESCl, MEMCl or SMCl)        in the conditions according with known procedures in organic        synthesis (for example: Imidazole, DIPEA, DMAP or Et₃N in DMF or        CH₂Cl₂), other protecting groups are also contemplated in the        invention,    -   converting the terminal vinyl group at carbons 4 and 5 to an        aldehyde in compound 13. This conversion is carried out by        ozonolysis of the vinyl group (for example O₃, in CH₂Cl₂ at −78°        C.) or by formation of the corresponding dihydroxy derivative        (for example NMO, OsO₄ in THF:H₂O) and the diol was cleavaged        (for example NaIO₄ in THF:H₂O or Pb(OAc)₄ in toluene) to the        corresponding aldehyde,    -   chain extension at carbon 5 to give compound 14. In the        illustrated example, the selected reagent (CH₃C(O)N(CH₃)OCH₃) is        converted into the corresponding enolate ([(CH₃)₃Si]₂NLi in THF        at −78° C.) and added to 13 at low temperature (−78° C.) to give        14, alternative procedures for chain extension known to the        person skilled in the art can also be used to achieve the same        purpose,    -   further protection at the 5-hydroxy group to give compound 15.        This protection is carried out with the related reagent of the        selected protecting group (such as TBSOTf) in the conditions        (2,6-lutidine in CH₂Cl₂) according to known procedures.        Alternative protecting groups can also be used,    -   oxidation of the hydroxy group at carbon 7 to afford        compound 16. This oxidation is carried out with the        corresponding reagent (such as Dess-Martin periodinane) in the        conditions according with known procedures in organic synthesis        (for example in CH₂Cl₂),    -   deprotection at the 13-protected hydroxy group to give        terminally deprotected compound 17. This deprotection is carried        out with the related reagent (for example DDQ) for the selected        protecting group (for example PMB) in the conditions according        with known procedures (for example in CH₂Cl₂:H₂O),    -   formation of a terminal olefin group by extension with carbons        14 and 15 to give compound 18. This transformation is performed        in two steps: a) oxidation of the primary hydroxy group into the        corresponding aldehyde with the selected reagent (for example        Dess-Martin periodinane) and b) formation of the cis double        bound through a Wittig or Horner-Wadsworth-Emmons reaction in        the standard conditions, alternative procedures for chain        extension known to the person skilled in the art can also be        used to achieve the same purpose,    -   formation, if not already present, of the 7-keto substituent of        compound 19. This oxidation is carried out with the        corresponding reagent (such as Dess-Martin periodinane) in the        conditions according with known procedures in organic synthesis        (for example in CH₂Cl₂),    -   chain extension with carbons 1 and 2 if not already present in        compound 19. This extension is carried out with the        corresponding reagent (such as BrMgEt) in the conditions        according with known procedures in organic synthesis (for        example in THF),    -   partial or complete deprotection to a compound 20 or 4/3. This        deprotection is carried out with the related reagent (such as        TBAF and AcOH) for the selected protecting group (for example        TBS) in the conditions according with known procedures (for        example in CH₂Cl₂),    -   and optional derivatisation to a derivative shown as compound        (1), where at least one R is not hydrogen, for example by        reaction with Ac₂O, an alkylcarboxylate chloride or anhydride in        the presence of the corresponding base (for example Et₃N) in any        suitable solvent such as CHCl₃.

Additionally, different isomerically synthetic myriaporones are preparedfrom the intermediate compound 8 by using a different stereospecificleaving group, for example by using (S)-oxazolidinone instead of(R)-oxazolidinone. The route for producing these compounds is depictedin Scheme 2.

The reaction scheme 2 involves the same reactions as those of scheme I,with a different stereochemistry in the oxazolidinone 9.

A purpose of the invention is to provide a first total synthesis ofmyriaporones 3 and 4 and from these compounds or previous intermediatesobtain other compounds of formula I. The synthesis should preferablymake it possible to obtain the largest possible quantities ofmyriaporones 3 and 4 by simple ways and means. The synthesis should alsoallow the preparation of the largest possible number of specificderivatives of myriaporones 3 and 4. In addition, the synthesis shouldpreferably proceed stereoselectively, so that four diastereoisomers ofmyriaporones 3 and 4 can be obtained in pure form. A further purpose ofthe invention is to provide the kind of total synthesis intermediatesthat will make the synthesis as flexible as possible and thus enable thepreparation of a large number of derivatives.

In the previous reaction schemes, the hydroxy protecting groups R¹, R²,R⁴, R⁶, and R⁷ may be any of the examples of hydroxy protecting groupsreported in “Protective Groups in Organic Synthesis”, T. W. Greene, P.G. Wuts, Ed. Wiley-Interscience, 3^(rd) Edition. Examples of hydroxyprotecting groups are given in the following list: protection for —OHgroup abbreviation ethers methyl methoxymethyl MOM benzyloxymethyl BOMmethoxyethoxymethyl MEM 2-(trimethylsilyl)ethoxymethyl SEMmethylthiomethyl MTM phenylthiomethyl PTM azidomethyl cyanomethyl2,2-dichloro-1,1-difluoroethyl 2-chloroethyl 2-bromoethyltetrahydropyranyl THP 1-ethoxyethyl EE phenacyl 4-bromophenacylcyclopropylmethyl allyl propargyl isopropyl cyclohexyl t-butyl benzyl2,6-dimethylbenzyl 4-methoxybenzyl MPM or PMB o-nitrobenzyl2,6-dichlorobenzyl 3,4-dichlorobenzyl 4-(dimethylamino)carbonylbenzyl4-methylsuflinylbenzyl Msib 9-anthrylmethyl 4-picolylheptafluoro-p-tolyl tetrafluoro-4-pyridyl trimethylsilyl TMSt-butyldimethylsilyl TBDMS t-butyldiphenylsilyl TBDPS triisopropylsilylTIPS esters aryl formate aryl acetate aryl levulinate aryl pivaloateArOPv aryl benzoate aryl 9-fluorocarboxylate aryl methyl carbonate1-adamantyl carbonate t-butyl carbonate BOC-OAr 4-methylsulfinylbenzylcarbonate Msz-Oar 2,4-dimethylpent-3-yl carbonate Doc-Oar aryl2,2,2-trichloroethyl carbonate aryl vinyl carbonate aryl benzylcarbonate aryl carbamate dimethylphosphinyl Dmp-OArdimethylphosphinothioyl Mpt-OAr diphenylphosphinothioyl Dpt-Oar arylmethanesulfonate aryl toluenesulfonate aryl 2-formylbenzenesulfonate

Preferred R², R⁴, R⁶ and R⁷ are TBS (tBuMe₂Si—), TBDPS (tBuPh₂Si—), TES(Et₃Si—), MOM (CH₃OCH₂—), MEM (CH₃OCH₂CH₂OCH₂—), SEM((CH₃)₃SiCH₂CH₂OCH₂—) and Ac—, and more preferred are TBS and TBDPS. Itis also preferred that R², R⁴, R⁶ and R⁷ are the same protecting group.Preferred R¹ is PMB (p-MeO-Ph-CH₂—). The protecting and deprotectingreactions presented in previous reaction schemes are performed accordingto the state of the art.

The group R³ shown in the schemes is selected from the group consistingof H, OH, ═O, OR′, OSiR′, OSOR′, OSO₂R′, OCOR′, OCOOR′, CONR′, NHR′ andNR′R′. R′ has the same meaning as defined in formula I. Preferred R³ isa hydroxy or ═O.

The group shown as R⁵ in the schemes is selected from the groupconsisting of H, SOR′, SO₂R′, C(═O)R′, C(═O)OR′, C(═O)NR′, substitutedor unsubstituted alkyl, substituted or unsubstituted alkenyl,substituted or unsubstituted alkynyl, aryl, heteroaryl or aralkyl. AndR′ has the same meaning as defined in formula I. Preferred R⁵ is C₁-C₆and more preferred is ethyl.

The identity of compounds 9. and 21 can be changed obtaining for otherways compounds 11 and 23 from compound 8, according to the state of theart.

The relative stereochemistry at C-8-C-12 of compounds 3 and 4 wasassumed as the same as described in Pat. No. 5,514,708, 1996 on thebasis of coupling constant comparisons cited there. Besides, thestereochemistry of the starting material 6 written above was alreadyindicated by W. R. Roush et al., Org. Lett. 1999, 1, 95.

To support this information, the stereochemistry of these carbons wasassigned on the basis of NOESY and COSY studies of the intramolecularepoxide opened product 33 which was prepared from 11a in two steps(Scheme 3).

The absolute configuration of C-8 to C-12 has been readily identified byNOE experiments. A syn relative stereochemistry at C-11-C-12 was deducedfrom the coupling constant (J=1.5 Hz). A NOE signal between H-11 andH-14 indicates both must be in axial position.

An anti relative stereochemistry at C-6-C-7 was deduced from the smallvalue of the coupling constant of the acetonide 34 prepared fromcompound 11a (Scheme 4).

Finally, the stereochemistry of compounds 3a, 3b, 4a and 4b at C-5 wasassigned by conversion of the 1,3 diol of 15a and 15b to the 1,3-syn andanti acetonides respectively (scheme 5).

The stereochemistry of syn- and anti-1,3-diol acetonides was assignedaccording to S. D. Rychnovsky et al., J. Org. Chem. 1993, 58, 3511-3515,from the ¹³C chemical shifts of the acetal methyl groups. In general,the syn-1,3-diol acetonides have acetal methyl shifts at 19 and 30 ppmrespectively, while the anti-acetonides have both methyl shifts at about25 ppm. Indeed, we have tested the reability of this method since the¹³C NMR spectrum of the syn-acetonide 35b shows an axial methyl group atca. 20.2 ppm and an equatorial methyl group at ca. 30.0 ppm, whereas the¹³C spectrum of the anti-acetonide 35a shows both methyl groups at 24.4and 25.2 ppm.

Unfortunately, it could not be possible to determine the stereochemistryof 3c, 3d, 4c and 4d by preparing the acetonides of 26a and 26b sincethese compounds could not be separate by conventional methods. In thesecases, the configuration at C-5 position was stablished by conversion of11a into the 1,3-diols 38a and 38b which can be easily separated. Afterseveral reactions, these compounds are leaded to the known intermediates27c and 27d respectively. The stereochemistry of these compounds wasdetermined from the ¹³C chemical shifts of the corresponding acetonides36a (δ=24.1, 25.0 ppm) and 36b (δ=19.7, 29.9 ppm) (scheme 6).

The relative stereochemistry for H-5 and H-6 at myriaporones 3 and 4 wasconcluded by studing the coupling constants between the protons on thesix-membered rings hemiketal monoprotected myriaporones 20 and 31(scheme 7).

For 20a and 31b, H-4 at δ 1.73 and 1.58 ppm respectively, both withcoupling constants of 14.5, 3.5 Hz was assigned to be axial. The othersH-4 with upfield chemical shift at δ 2.02 and 2.03 ppm for eachcompound, have coupling constants of 14.0, 3.5 Hz and 14.5, 3.5 Hz,respectively. These value indicate the proton H-5 should be equatorial.

Similary, the coupling constants between H-5 and H-6 are, in both cases,around 2 Hz, indicating again that H-5 should be equatorial. Thus, therelative stereochemistry for H-5 and H-6 is concluded to be syn.

On the other hand, the ¹H NMR spectra of compounds 20b and 31a aredifferent from compounds 20a and 31b in coupling constants and,primarily, in the chemical shift. For these compounds, the couplingconstants between H-4 (ax) and H-5 are around 12, 13 Hz, indicating H-5should be in axial.

In addition, the coupling constants between H-5 and H-6 are inconcordance with the fact that H-6 is placed in axial to minimizeinteraction and therefore, the relative stereochemistry for H-5 and H-6is concluded to be anti.

The stereochemistry at C-3 in the hemiketal compounds could not beassigned by NOE experiments. In the scheme 7, the hemiketal hidroxigroup at C3 was arbitrarily placed equatorial.

Another especially preferred embodiment of the present invention ispharmaceutical compositions useful as antitumor agents which contain asactive ingredient a compound or compounds of the invention, as well asthe processes for their preparation.

An important feature of the above described compounds of formula I istheir bioactivity and in particular their cytotoxic activity. With thisinvention we provide novel pharmaceutical compositions of compounds ofgeneral formula I that possess cytotoxic activity, and their use asantitumor agents. Thus the present invention further providespharmaceutical compositions comprising a compound of this invention, apharmaceutically acceptable salts, derivatives, prodrugs orstereoisomers thereof with a pharmaceutically acceptable carrier.

Examples of pharmaceutical compositions include any solid (tablets,pills, capsules, granules etc.) or liquid (solutions, suspensions oremulsions) with suitable composition for oral, topical or parenteraladministration.

Administration of the compounds or compositions of the present inventionmay be any suitable method, such as intravenous infusion, oralpreparation, intraperitoneal and intravenous preparation. We prefer thatinfusion times of up to 24 hours are used, more preferably 2-12 hours,with 2-6 hours most preferred. Short infusion times which allowtreatment to be carried out without an overnight stay in hospital areespecially desirable. However, infusion may be 12 to 24 hours or evenlonger if required. Infusion may be carried out at suitable intervals ofsay 1 to 4 weeks. Pharmaceutical compositions containing compounds ofthe invention may be delivered by liposome or nanosphere encapsulation,in sustained release formulations or by other standard delivery means.

The correct dosage of the compounds will vary according to theparticular formulation, the mode of application, and the particularsitus, host and tumour being treated. Other factors like age, bodyweight, sex, diet, time of administration, rate of excretion, conditionof the host, drug combinations, reaction sensitivities and severity ofthe disease shall be taken into account. Administration can be carriedout continuously or periodically within the maximum tolerated dose.

The compounds and compositions of this invention may be used with otherdrugs to provide a combination therapy. The other drugs may form part ofthe same composition, or be provided as a separate composition foradministration at the same time or a different time.

Antitumoral activities of these compounds include among othersleukaemias, lung cancer, colon cancer, kidney cancer, prostate cancer,ovarian cancer, breast cancer, pancreas cancer, cervix cancer, sarcomasand melanomas.

The present invention will be further explained with the followingexamples which are not limiting. As can be seen, this methodology allowsfor the synthesis of myriaporone compounds with the desiredstereospecificity.

EXAMPLES Example 1 Compound 7a

To a solution of 6 (3.51 g, 7.8 mmol) in CH₂Cl₂ (40 mL) was addedimidazole (1.59 g, 23.4 mmol) and TBSCl (1.76 g, 11.7 mmol) at 23° C.The reaction mixture was stirred at 23° C. for 3 h. HCl 0.1 N was addeduntil pH=4-5, and the mixture was extracted with CH₂Cl₂ (2×). Thecombined organic layers were dried over Na₂SO₄, filtered, andconcentrated under reduced pressure. The residue was purified bychromatography on silica gel (Hex:EtOAc, 10:1) to obtain compound 7a(3.44 g, 78%) as a colourless oil.

¹H NMR (300 MHz, CDCl₃) δ 7.23 (d, J=8.7 Hz, 2H), 6.86 (d, J=8.7 Hz,2H), 5.83 (m, 1H), 4.99 (dd, J=10.5, 1.8 Hz, 1H), 4.86 (dd, J=17.4, 2.1Hz, 1H), 4.42 (s, 2H), 3.80 (s, 3H), 3.44 (m, 2H), 3.33 (d, J=6.6 Hz,1H), 2.47 (d, J=9.6 Hz, 1H), 2.44 (m, 1H), 1.75 (m, 1H), 1.08 (d, J=6.6Hz, 3H), 0.91 (s, 9H), 0.88 (s, 9H), 0.13 (s, 3H), 0.04 (s, 3H), 0.02(s, 3H), 0.01 (s, 3H). ¹³C NMR (75 MHz, CDCl₃) δ 159.1, 136.2, 130.3,129.1, 117.1, 113.7, 72.9, 72.6, 64.9, 64.6, 63.9, 55.2, 51.3, 33.1,25.9, 25.8, 18.2, 18.1, 14.9, 13.3, −4.2, −5.3, −5.4, −5.5. MS (ESI)m/z: 587 (M+23)⁺.

[α]²⁵ _(D) −9.5 (c 0.52, CH₂Cl₂).

R_(f)=0.61 (Hex:EtOAc, 4:1).

Example 2 Compound 7b

Compound 7b was prepared as a colourless oil, in the same way as 7b fromthe corresponding precursor of 6, according to the procedure describedby W. Roush et al., Org. Lett. 1999, 1, 95) by using TESOTf instead ofTBSOTf in equivalent amounts for the secondary alcohol protection step.

¹H NMR (300 MHz, CDCl₃) δ 7.24 (d, J=8.7 Hz, 2H), 6.87 (d, J=8.7 Hz,2H), 5.92-5.80 (m, 1H), 5.02 (dd, J=10.2, 1.8 Hz, 1H), 4.90 (dd, J=17.4,1.8 Hz, 1H), 4.42 (s, 2H), 3.78 (s, 3H), 3.56-3.42 (m, 3H), 3.38-3.34(m, 2H), 2.52 (d, J=9.0 Hz, 1H), 2.27-2.23 (m, 1H), 1.81-1.76 (m, 1H),1.27 (s, 3H), 1.10 (d, J=6.6 Hz, 3H), 0.98 (t, J=7.8 Hz, 9H), 0.90 (s,9H), 0.71-0.62 (m, 6H), 0.05 (s, 3H), 0.04 (s, 3H).

¹³C NMR (75 MHz, CDCl₃) δ 159.1, 136.4, 130.2, 129.0, 116.8, 113.6,76.9, 72.8, 72.6, 64.7, 64.6, 63.8, 55.0, 51.1, 33.2, 25.7, 18.0, 14.8,13.1, 6.9, 4.8, −5.3, −5.5.

MS (ESI) m/z: 587 (M+23)⁺, 565 (M+1)⁺.

R_(f)=0.62 (Hexane:EtOAc, 4:1).

Example 3 Compound 7c

To a solution of 6 (450 mg, 1 mmol) in CH₂Cl₂ (20 mL) was added DIPEA(1.74 mL, 10 mmol) and MOMBr (0.45 mL, 5 mmol) at 0° C. The reactionmixture was stirred at 0° C. for 4 h. Then, a saturated aqueous solutionof NH₄Cl was added and the mixture was extracted with CH₂Cl₂ (2×30 mL).The combined organic layers were dried over Na₂SO₄, filtered, andconcentrated under reduced pressure. The residue was purified bychromatography on silica gel (Hex:EtOAc, 10:1) to obtain compound 7c(250 mg, 51%) as a colourless oil.

¹H NMR (300 MHz, CDCl₃) δ 7.24 (d, J=8.4 Hz, 2H), 6.87 (d, J=8.4 Hz,2H), 5.90-5.78 (m, 1H), 5.04 (dd, J=10.2, 2.1 Hz, 1H), 4.95 (dd, J=17.4,2.1 Hz, 1H), 4.56 (s, 2H), 4.43 (s, 2H), 3.80 (s, 3H), 3.51-3.40 (m,1H), 3.37-3.34 (m, 4H), 3.33 (s, 3H), 2.52 (d, J=9.3 Hz, 1H), 2.43-2.40(m, 1H), 1.79-1.65 (m, 1H), 1.25 (s, 3H), 1.09 (d, J=6.6 Hz, 3H), 0.91(s, 9H), 0.14 (s, 3H), 0.04 (s, 3H).

¹³C NMR (75 MHz, CDCl₃) δ 159.4, 136.4, 130.6, 129.4, 117.6, 114.0,96.8, 78.2, 73.1, 72.7, 69.0, 64.8, 64.7, 55.6, 55.5, 49.2, 33.4, 26.2,18.5, 15.2, 13.5, −3.9, −5.3.

R_(f)=0.52 (Hex:EtOAc, 4:1).

Example 4 Compound 7d

To a solution of the corresponding diol, (581 mg, 1.73 mmol) in CH₂Cl₂(20 mL) was added 2,6-lutidine (0.61 g, 5.2 mmol) and t-Bu₂Si(OTf)₂(9.48 mL mL, 2.6 mmol) at 0° C. The reaction mixture was stirred at 0°C. for 2 h. Then, a saturated aqueous solution of NH₄Cl was added andthe mixture was extracted with CH₂Cl₂ (2×30 mL). The combined organiclayers were dried over Na₂SO₄, filtered, and concentrated under reducedpressure. The residue was purified by flash column chromatography onsilica gel (Hex:EtOAc, 10:1) to obtain compound 7d (330 mg, 40%) as acolourless oil.

¹H NMR (300 MHz, CDCl₃) d 7.23 (d, J=8.7 Hz, 2H), 6.87 (d, J=8.7 Hz,2H), 6.40 (ddd, J=17.1, 9.9, 8.7 Hz, 1H), 5.10 (dd, J=10.5, 1.8 Hz, 1H),5.06 (dd, J=17.1, 1.8 Hz, 1H), 4.41 (s, 2H), 4.35 (dd J=11.1, 3.0 Hz,1H), 4.06 (d, J=3.0 Hz, 1H), 4.00 (dd, J=11.1, 2.4 Hz, 1H), 3.80 (s,3H), 3.34 (d, J=6.3 Hz, 2H), 2.72 (d, J=9.3 Hz, 1H), 2.41-2.37 (m, 1H),1.78-1.73 (m, 1H), 1.28 (s, 3H), 1.09 (d, J=6.6 Hz, 3H), 1.07 (s, 9H),1.05 (s, 9H).

¹³C NMR (75 MHz, CDCl₃) δ 159.4, 136.9, 130.7, 129.2, 116.9, 114.0,79.6, 73.1, 72.8, 70.4, 63.7, 62.3, 55.5, 47.0, 33.3, 28.6, 27.7, 23.5,21.0, 15.1.

MS (ESI) m/z: 499 (M+23)⁺.

R_(f)=0.41 (Hex:EtOAc, 4:1).

Example 5 Compound 8a

Over a solution of 7a (21.94 g, 38.7 mmol) in CH₂Cl₂ (150 mL) wasbubbled a current of O₃ during 50 min at −78° C. Then, Ph₃P (30.45 g,116.1 mmol) was added and the mixture was allowed to warm to roomtemperature, and the stirring was continued for 12 h. The mixture wasconcentrated under reduced pressure and the residue was purified byflash column chromatography on silica gel (Hex:EtOAc, 20:1) to affordcompound 8a (15.82 g, 72%) as a colourless oil.

¹H NMR (300 MHz, CDCl₃) δ 9.67 (d, J=3.0 Hz, 1H), 7.20 (d, J=8.4 Hz,2H), 6.84 (d, J=8.4 Hz, 2H), 4.38 (m, 2H), 3.84 (dd, J=10.2, 5.1 Hz,1H), 3.80 (s, 3H), 3.69 (m, 2H), 3.41 (dd, J=9.3, 5.1 Hz, 1H), 3.31 (t,J=9.0 Hz, 1H), 2.59 (d, J=9.3 Hz, 1H), 2.50 (m, 1H), 1.81 (m, 1H), 1.30(s, 3H), 1.06 (d, J=6.3 Hz, 3H), 0.86 (s, 18H), 0.14 (s, 3H), 0.04 (s,3H), 0.02 (s, 3H), 0.01 (s, 3H).

¹³C NMR (75 MHz, CDCl₃) δ b 203.8, 159.5, 130.3, 129.4, 114.0, 76.5,73.2, 73.0, 65.1, 64.0, 60.1, 57.9, 55.4, 33.6, 26.0, 26.0,18.3, 15.0,13.0, −4.0, −5.2, −5.3, −5.5.

MS ESI) m/z: 589 (M+23)⁺.

[α]²⁵ _(D) −11.6 (c 0.50, CH₂Cl₂).

R_(f)=0.59 (Hex:EtOAc, 4:1).

Example 6 Compound 8b

To a solution of 7b (0.86 g, 1.52 mmol) in THF:H₂O (10:1, 22 mL) wasadded NMO (0.623 g, 5.32 mmol) and OSO₄ (4.56 mL, 0.456 mmol, 0.1 M in^(t)BuOH) at 23° C. and the reaction mixture was stirred at 23° C.overnight. Florisil (6 g), NaHSO₃ (6 g), and EtOAc (100 mL) were addedand the mixture was stirred vigorously during 30 min. The mixture wasfiltered through a pad of Celite, and the filtrate was concentrated toprovide the corresponding diol. To a solution of this diol in THF (10mL) was added a solution of NaIO₄ (1.95 g, 9.12 mmol) in H₂O (8 mL) at0° C. and the mixture was stirred at 23° C. for 1 h. The reaction wasquenched by addition of a saturated aqueous solution of NH₄Cl (20 mL)and then, extracted with CH₂Cl₂ (2×20 mL). The combined organic layerswere dried over Na₂SO₄, filtered, and concentrated under reducedpressure. The residue was purified by flash column chromatography onsilica gel (Hex:EtOAc, 10:1) to afford compound 8b (0.67 g, 78%) as acolourless oil.

¹H NMR (300 MHz, CDCl₃) δ 9.68 (d, J=2.4 Hz, 1H), 7.17 (d, J=8.4 Hz,2H), 6.83 (d, J=8.4 Hz, 2H), 4.36 (q, J=11.4 Hz, 2H), 3.83 (dd, J=10.2,5.1 Hz, 1H), 3.76 (s, 3H), 3.74 (d, J=6.3 Hz, 1H), 3.67 (dd, J=10.2, 5.7Hz, 1H), 3.39 (dd, J=9.3, 5.1 Hz, 1H), 3.30 (t, J=9.0 Hz, 1H), 2.60 (d,J=9.3 Hz, 1H), 2.47-2.40 (m, 1H), 1.82-1.78 (m, 1H), 1.28 (s, 3H), 1.04(d, J=6.6 Hz, 3H), 0.92 (t, J=7.8 Hz, 9H), 0.85 (S, 9H), 0.85 (s, 9H),0.62 (q, J=7.8 Hz, 6H), 0.01, (s, 3H), 0.00 (s, 3H).

¹³C NMR (75 MHz, CDCl₃) δ 203.4, 159.1, 129.9, 129.0, 113.6, 75.9, 72.8,72.6, 64.9, 63.5, 59.7, 57.4, 55.0, 33.3, 25.6, 17.9, 14.6, 12.5, 6.7,4.6, −5.5, −5.7.

MS (ESI) m/z: 589 (M+23)⁺.

R_(f)=0.54 (Hexane:EtOAc, 4:1).

Example 7 Compound 9

Compound 9 was prepared following the procedure described by D. A. Evanset al., J. Am. Chem. Soc. 1984, 106, 4261-4263.

¹H NMR (300 MHz, CDCl₃) δ 7.21 (m, 1H), 7.12 (m, 1H), 4.44 (m, 1H), 4.20(m, 2H), 2.36 (m, 1H), 1.91 (dd, J=6.6, 1.2 Hz, 3H), 0.88 (d, J=6.9 Hz,3H), 0.83 (d, J=6.9 Hz, 3H).

Example 8 Compound 10a

To a solution of 9 (17.75 g, 0.09 mol) in CH₂Cl₂ (270 mL) was addedBu₂BOTf (99 mL, 1M in CH₂Cl₂, 0.099 mol) and Et₃N (17.56 mL, 0.126 mol)at −78° C. The reaction mixture was stirred 1 h at −78° C., 15 min at 0°C. and recooled at −78° C. This solution was added in three portion in 5h over a solution of 8a (17.18 g, 0.03 mol) in CH₂Cl₂ (100 mL) at 0° C.and the mixture was stirred at −30° C. for an additional 12 h. Then,saturated aqueous solution of NH₄Cl (300 mL) was added and the reactionwas extracted with CH₂Cl₂ (2×200 mL). The combined organic layers weredried over Na₂SO₄, filtered, and concentrated under reduced pressure.The residue was dissolved in 400 mL of ether, 200 mL of buffer solutionand 200 mL of H₂O₂ and the mixture was stirred at 0° C. for 1 h. Then,the reaction was extracted and the organic phase was washed with asaturated aqueous solution of NaHCO₃ (200 mL) and brine (200 mL). Theorganic layer were dried over Na₂SO₄, filtered, and concentrated underreduced pressure. The residue was purified by flash columnchromatography on silica gel (Hex:EtOAc, from 10:1 to 2:1) to affordcompound 10a (21 g, 92%) as a colourless oil.

¹H NMR (300 MHz, CDCl₃) δ 7.19 (d, J=8.4 Hz, 2H), 6.85 (d, J=8.4 Hz,2H), 5.93 (m, 1H), 5.41 (d, J=17.1 Hz, 1H), 5.28 (d, J=9.3 Hz, 1H), 4.92(t, J=9.6 Hz, 1H), 4.63 (dddd, J=9.3, 6.3, 5.1, 1.5 Hz, 1H), 4.43 (s,3H), 4.34 (m, 1H), 4.12 (m, 2H), 3.85 (m, 1H), 3.80 (s, 3H), 3.73 (m,2H), 4.44 (m, 2H), 2.58 (d, J=9.3 Hz, 1H), 2.30 (m,. 1H), 1.81 (m, 1H),1.38 (s, 3H), 1.10 (d, J=6.6 Hz, 3H), 0.93 (s, 9H), 0.87 (s, 9H), 0.84(d, J=7.5 Hz, 3H), 0.80 (d, J=6.9 Hz, 3H), 0.17 (s, 3H), 0.12 (s, 3H),0.09 (s, 3H).

¹³C NMR (75 MHz, CDCl₃) δ 172.0, 159.0, 153.3, 135.3, 129.9, 128.6,113.7, 77.4, 72.6, 71.0, 64.0, 63.4, 62.6, 59.8, 58.4, 58.0, 55.2, 51.2,45.2, 40.1, 33.6, 26.7, 28.3, 27.8, 26.1, 25.8, 18.3, 17.9, 15.1, 14.6,14.3, 13.1, −4.4, −5.4, −5.5, −5.6.

MS (ESI) m/z: 786 (M+23)⁺.

[α]²⁵ _(D) +3.1 (c 0.53, CH₂Cl₂).

R_(f)=0.35 (Hex:EtOAc, 4:1).

Example 9 Compound 10b

The title compound was prepared as described above from 8b (1.2 g, 2.11mmol). Chromatography (SiO₂,) provided 10b (1.16 g, 80%) as a colourlessoil.

¹H NMR (300 MHz, CDCl₃) δ 7.20 (d, J=8.4 Hz, 2H), 6.84 (d, J=8.4 Hz,2H), 5.85-6.03 (m, 1H), 5.19-5.44 (m, 2H), 4.93 (t, J=9.3 Hz, 1H),4.59-4.64 (m, 1H), 4.42-4.46 (m, 1H), 4.42 (s, 2H), 4.19-4.36 (m, 4H),4.05-4.15 (m, 2H), 3.80 (s, 3H), 3.65-3.83 (m, 3H), 3.40-3.46 (m, 1H),2.57 (d, J=9.3 Hz, 1H), 2.27-2.36 (m, 1H), 1.78-1.86 (m, 1H), 1.56-1.64(m, 1H), 1.37 (s, 3H), 1.28-1.38 (m, 6H), 0.92 (s, 9H), 0.88-0.99 (m,6H), 0.62-0.68 (m, 9H), 0.09 (s, 3H), 0.04 (s, 3H).

R_(f)=0.42 (Hex:EtOAc, 4:1).

Example 10 Compound 11a

To a solution of 10a (14.5 g, 18.9 mmol) in THF:H₂O (5:1, 120 mL), LiBH₄(141.9 mL, 2.0 M in THF, 283.7 mmol,) was added at 0° C. The reactionmixture was stirred 30 min at 0° C. and 6 h at 23° C. Saturated aqueoussolution of NH₄Cl (150 mL) was added and the mixture was extracted withEtOAc (3×150 mL). The combined organic layers were dried over Na₂SO₄,filtered, and concentrated under reduced pressure. The residue wasdissolved in 400 mL of ether, 200 mL of buffer solution and 200 mL ofH₂O₂ and the mixture was stirred at 0° C. for 2 h. Then, the reactionwas extracted and the organic phase was washed with a saturated aqueoussolution of NaHCO₃ (2×200 mL). The organic layer were dried over Na₂SO₄,filtered, and concentrated under reduced pressure. The residue waspurified by flash column chromatography on silica gel (Hex:EtOAc 5:1) toafford compound 11a (10.5 g, 87%) as a colourless oil.

¹H NMR (300 MHz, CDCl₃) δ 7.22 (d, J=8.4 Hz, 2H), 6.87 (d, J=8.4 Hz,2H), 5.84 (m, 1H), 5.21 (d, J=8.7 Hz, 1H), 5.14 (d, J=17.4 Hz, 1H), 4.42(s, 2H), 4.19 (m, 1H), 3.84 (m, 1H), 3.80 (s, 3H), 3.75 (m, 1H), 3.61(m, 2H), 3.48 (m, 2H), 3.36 (m, 2H), 2.53 (d, J=9.3 Hz, 1H), 2.27 (m,1H), 1.80 (m, 1H), 1.32 (s, 3H), 1.05 (d, J=6.9 Hz, 3H), 0.91 (s, 9H),0.88 (s, 9H), 0.15 (s, 3H), 0.09 (s, 3H), 0.05 (s, 3H), 0.04 (s, 3H),

¹³C NMR (75 MHz, CDCl₃) δ 159.5, 137.6, 130.3, 129.4, 118.3, 114.0,73.2, 73.0, 71.2, 64.9, 64.4, 60.4, 55.5, 51.1, 47.0, 33.5, 29.9, 26.4,26.3, 26.0, 18.4, 18.2, 15.0, 14.0, −4.2, −5.1, −5.2.

MS (ESI) m/z: 662 (M+23)⁺.

[α]²⁵ _(D) +0.7 (c 0.54, CH₂Cl₂).

R_(f)=0.2 (Hex:EtOAc, 4:1).

Example 11 Compound 11b

The title compound was prepared as described above from 10b (1.53 g, 2mmol). Chromatography (SiO₂,) provided 11b (1 g, 80%) as a colourlessoil.

¹H NMR (300 MHz, CDCl₃) δ 7.22 (d, J=8.7 Hz, 2H), 6.87 (d, J=8.7 Hz,2H), 5.92-5.80 (m, 1H), 5.92-5.80 (m, 1H), 5.21 (dd, J=10.2, 2.1 Hz,1H), 5.14 (dd, J=17.1, 2.1 Hz, 1H), 4.40 (s, 2H), 4.19-4.16 (m, 1H),3.84 (dd, J=6.0, 1.5, 1H), 3.80 (s, 3H), 3.72 (dd, J=6.3, 2.4 Hz, 1H),3.62 (d, J=4.5 Hz, 1H), 3.56 (d, J=3.6, 1H), 3.52-3.48 (m, 1H),3.38-3.33 (m, 2H), 2.53 (d, J=9.0 Hz, 1H), 2.27-2.22 (m, 1H), 1.83-1.78(m, 1H), 1.73-1.67 (m, 1H), 1.30 (s, 3H), 1.04 (d, J=6.9 Hz, 3H), 0.95(t, J=7.8 Hz, 9H), 0.87 (s, 9H), 0.67 (q, J=7.8 Hz, 6H), 0.05 (s, 3H),0.04 (s, 3H).

¹³C NMR (75 MHz, CDCl₃) δ 159.2, 137.4, 130.1, 129.1, 118.0, 113.7,77.4, 72.9, 72.7, 71.1, 64.9, 64.3, 64.2, 60.2, 55.2, 51.0, 46.6, 33.3,25.7, 17.9, 14.8, 13.5, 6.8, 4.7, −5.3, −5.5.

Rf=0.18 (Hex:EtOAc 4:1).

Example 12 Compound 12a

To a solution of 11a (7.43 g, 11.6 mmol) in CH₂Cl₂ (100 mL) was addedimidazole (3.16 g, 46.4 mmol) and TBSCl (3.48 g, 23.2 mmol) at 23° C.The reaction mixture was stirred at 23° C. for 4 h. 0.1N HCl was addeduntil pH═4-5, and the reaction was extracted with CH₂Cl₂ (2×150 mL). Thecombined organic layers were dried over Na₂SO₄, filtered, andconcentrated under reduced pressure. The residue was purified by flashcolumn chromatography on silica gel (Hex:EtOAc, from 10:1 to 4:1) toobtain compound 12a (8.47 g, 97%) as a colourless oil.

¹H NMR (300 MHz, CDCl₃) δ 7.22 (d, J=8.6 Hz, 2H), 6.86 (d, J=8.6 Hz,2H), 5.86 (m, 1H), 5.07 (m, 2H), 4.41 (m, 2H), 4.29 (br s, 1H), 3.88 (m,1H), 3.80 (s, 3H), 3.74 (m, 1H), 3.62 (m, 2H), 3.48 (m, 1H), 3.34 (d,J=6.8 Hz, 2H), 3.17 (d, J=4.9 Hz, 1H), 2.55 (d, J=9.2 Hz, 1H), 2.26 (m,1H), 1.78 (m, 2H), 1.32 (s, 3H), 1.06 (d, J=6.6 Hz, 3H), 0.92 (s, 9H),0.88 (s, 9H), 0.87 (s, 9H), 0.16 (s, 3H), 0.10 (s, 3H), 0.05 (s, 3H),0.03 (s, 9H).

¹³C NMR (75 MHz, CDCl₃) δ 159.4, 138.0, 130.5, 129.2, 117.1, 114.0,77.4, 73.1, 72.8, 69.4, 65.0, 64.8, 64.5, 60.7, 55.4, 51.9, 46.9, 33.7,29.9, 26.3, 26.2, 26.1, 18.6, 18.5, 18.1, 15.1, 13.5, −4.3, −5.0, −5.1,−5.2.

MS (ESI) m/z: 775 (M+23)⁺, 753 (M+1)⁺.

[α]²⁵ _(D) +3.0 (c 0.54, CH₂Cl₂).

R_(f)=0.66 (Hex:EtOAc, 4:1).

Example 13 Compound 12b

To a solution of 12a (500 mg, 0.663 mmol) in CH₂Cl₂ (30 mL) was addedDess-Martin periodinane (562 mg, 1.32 mmol) at 23° C. The reactionmixture was stirred at 23° C. for 3 h. Then, saturated aqueous solutionof NaHCO₃ (30 mL) was added and the mixture was extracted with CH₂Cl₂(3×40 mL). The combined organic layers were dried over Na₂SO₄, filtered,and concentrated under reduced pressure. The residue was purified byflash column chromatography on silica gel (Hex:EtOAc, 10:1) to obtaincompound 12b (414 mg, 83%) as a colourless oil.

¹H NMR (300 MHz, CDCl₃) δ 7.24 (d, J=8.4 Hz, 2H), 6.87 (d, J=8.4 Hz,2H), 5.78 (m, 1H), 5.23 (m, 2H), 4.42 (dd, J=16.2, 11.4, 2H), 4.02 (dd,J=10.2, 4.8 Hz, 1H), 3.81 (s, 3H), 3.74 (m, 1H), 3.61 (m, 2H), 3.33 (m,3H), 2.48 (d, J=9.3 Hz, 1H), 1.77 (m, 1H), 1.29 (s, 3H), 1.06 (d, J=6.6Hz, 3H), 0.87 (s, 9H), 0.86 (s, 9H), 0.84 (s, 9H), 0.11 (s, 3H), 0.04(s, 3H), 0.03, (s, 3H), 0.02, (s, 3H), −0.01, (s, 3H), −0.03 (s, 3H).

¹³C NMR (75 MHz, CDCl₃) δ 209.2, 159.1, 134.3, 130.2, 129.0, 119.3,113.7, 77.5, 72.7, 72.2, 64.3, 63.0, 62.3, 62.2, 61.1, 55.9, 55.2, 33.6,29.7, 26.0, 25.9, 25.8, 18.2, 18.1, 15.0, 12.2, −4.5, −5.2, −5.3, −5.4,−5.4, −5.5.

MS (ESI) m/z: 773 (M+23)⁺.

Example 14 Compound 12c

To a solution of 12a (1.5 g, 1.99 mmol) in CH₂Cl₂ (30 mL) was added Et₃N(5.55 mL, 39.82 mmol), DMAP (24 mg, 0.119 mmol) and Ac₂O (1.88 mL, 19.91mmol) at 0° C. The reaction mixture was stirred at 23° C. for 12 h.Then, a saturated aqueous solution of NaHCO₃ (50 mL) was added and andthe mixture was extracted with CH₂Cl₂ (3×30 mL). The combined organiclayers were washed with HCl 0.1 N, dried over Na₂SO₄, filtered, andconcentrated. The residue was purified by chromatography on silica gel(Hex:EtOAc, 10:1) to obtain compound 12c (1.12 g, 71%) as a colourlessoil.

¹H NMR (300 MHz, CDCl₃) δ 7.23 (d, J=8.5 Hz, 2H), 6.86 (d, J=8.5 Hz,2H), 5.66 (m, 1H), 5.48 (m, 2H), 5.09 (m, 2H), 4.42 (m, 2H), 3.80 (s,3H), 3.60 (m, 2H), 3.46 (m, 2H), 3.34 (m, 4H), 2.61 (m, 1H), 2.48 (d,J=9.1 Hz, 1H), 1.95 (s, 3H), 1.77 (m, 1H), 1.34 (s, 3H), 1.06 (d, J=6.6Hz, 3H), 0.91 (s, 9H), 0.88 (s, 9H), 0.86 (s, 9H), 0.11 (s, 3H), 0.05(s, 3H), 0.03 (s, 6H), 0.01 (s, 3H), −0.01 (s, 3H).

¹³C NMR (75 MHz, CDCl₃) δ 169.8, 159.4, 136.7, 130.6, 129.3, 118.3,114.0, 76.9, 73.0, 72.6, 70.6, 64.4, 59.9, 55.4, 52.5, 47.1, 33.4, 26.3,26.1, 26.1, 21.4, 18.6, 18.3, 15.2, 13.3, −4.1, −4.9, −5.0, −5.1, −5.2,−5.2.

MS (ESI) m/z: 817 (M+23)⁺, 812 (M+18)⁺.

R_(f)=0.63 (Hex:EtOAc, 4:1).

Example 15 Compound 12d

To a solution of 12a (215 mg, 0.285 mmol) in THF (5 mL) was added Py(0.46 mL, 5.7 mmol), DMAP (53 mg, 0.427 mmol) and (CF₃CO)₂O (0.40 mL,2.85 mmol) at 0° C. The reaction mixture was stirred at 23° C. for 12 h.Then, a saturated aqueous solution of NaHCO₃ (7 mL) was added and thereaction was extracted with CH₂Cl₂ (3×10 mL). The combined organiclayers were washed with HCl 0.1N (2×4 mL), dried over Na₂SO₄, filtered,and concentrated under reduced pressure. The residue was purified byflash column chromatography on silica gel (Hex:EtOAc, 18:1) to obtaincompound 12d (221 mg, 91%) as a colourless oil.

¹H NMR (300 MHz, CDCl₃) δ 7.22 (d, J=8.7 Hz, 2H), 6.87 (d, J=8.7 Hz,2H), 5.75 (m, 1H), 5.65 (m, 1H), 5.09 (m, 2H), 4.42 (s, 2H), 3.81 (s,3H), 3.47 (m, 8H), 2.78 (m, 1H), 2.51 (d, J=9.0 Hz, 1H), 2.11 (m, 1H),1.78 (m, 1H), 1.33 (s, 3H), 1.06 (d, J=6.9 Hz, 3H), 0.91 (s, 9H), 0.88(s, 18H), 0.12 (s, 3H), 0.06 (s, 3H), 0.03 (s, 3H), 0.01 (s, 6H), 0.00(s, 3H).

¹³C NMR (75 MHz, CDCl₃) δ 159.2, 156.0 (d, J_(C-F)=41.0 Hz), 134.6,130.2, 129.1, 119.4, 113.8, 76.0, 75.4, 72.9, 72.7, 64.3, 64.0, 63.8,59.3, 55.2, 51.6, 46.2, 33.1, 26.1, 25.9,18.3, 18.0, 14.8, 14.1, 13.2,−4.5, −5.0, −5.4, −5.5, −5.6, −5.7.

MS (ESI) m/z: 866 (M+18)⁺.

R_(f)=0.45 (Hex:EtOAc, 4:1).

Example 16 Compound 12e

The title compound was prepared as described above in example 12,starting from 11b (0.7 g, 1.09 mmol). Chromatography (SiO₂, Hex:EtOAc,15:1) provided 12e (661 g, 80%) as a colourless oil.

¹H NMR (300 MHz, CDCl₃) δ 7.22 (d, J=8.7 Hz, 2H), 6.86 (d, J=8.7 Hz,2H), 5.95-5.82 (m, 1H), 5.13-5.03 (m, 2H), 4.41(dd, J=15.6, 11.7 Hz,2H), 4.30-4.26 (m 1H), 3.86 (dd, J=13.8, 3.6 Hz, 1H), 3.79 (s, 3H), 3.74(dd, J=10.5, 6.3 Hz, 1H), 3.64 (d, J=5.7 Hz, 1H), 3.61 (d, J=6.3 Hz,1H), 3.50 (dd, J=9.9, 5.1 Hz, 1H), 3.34 (d, J=7.5 Hz, 2H), 3.18 (d,J=4.8 Hz, 1H), 2.56 (d, J=9.0 Hz, 1H), 2.32-2.23 (m, 1H), 1.85-1.79 (m1H), 1.74-1.71 (m, 1H), 1.31 (s, 3H), 1.06 (d, J=6.9 Hz, 3H), 0.97 (t,J=7.5 Hz, 9H), 0.89 (s, 9H), 0.88 (s, 9H), 0.68 (q, 7.2, 6H), 0.05 (s,3H), 0.04 (s, 6H), 0.03 (s, 3H).

¹³C NMR (75 MHz, CDCl₃) δ 158.9, 137.6, 130.0, 128.8, 116.6, 113.5,77.0, 72.6, 72.4, 69.1, 64.7, 64.6, 64.0, 60.2, 54.9, 51.3 46.2, 33.3,25.7,.25.6, 18.0, 17.7, 14.7, 12.9, 6.7, 4.5, −5.5, −5.7.

MS (ESI) m/z: 775 (M+23)⁺, 773 (M+1)⁺.

R_(f)=0.6 (Hex:EtOAc, 4:1).

Example 17 Compound 12f

To a solution of 11a (500 mg, 0.78 mmol) in CH₂Cl₂ (10 mL) was addedDIPEA (327 μL, 1.87 mmol) and MEMCl (107 μL, 0.94 mmol) at 0° C. Thereaction mixture was stirred at 23° C. for 14 h. Then, the reaction wasextracted with HCl 0.1N (10 mL) and the organic layer was dried overNa₂SO₄, filtered, and concentrated under reduced pressure. The residuewas purified by flash column chromatography on silica gel (Hex:EtOAc10:1) to obtain compound 12f (445 mg, 78%) as a colourless oil.

¹H NMR (300 MHz, CDCl₃) δ 7.22 (d, J=8.7 Hz, 2H), 6.87 (d, J=8.7 z, 2H),5.92-5.79 (m, 1H), 5.16-5.09 (m, 2H), 4.67 (s, 2H), 4.42 (dd, J=15.3,11.7 Hz, 2H), 4.23-4.18 (m, 1H), 4.85 (dd, J=10.5, 4.8 Hz, 1H), 3.80 (s,3H), 3.67-3.64 (m, 2H), 3.60 (d, J=5.7 Hz, 2H), 3.57-3.51 (m, 2H),3.49-3.40 (m, 2H), 3.37 (3, 3H), 2.56 (d, J=9.3 H), 2.45-2.40 (m, 1H),1.85-1.77 (m, 1H), 1.74-1.72 (m, 1H), 1.30 (s, 3H), 1.06 (d, J=6.6 Hz,3H), 0.91 (s, 9H), 0.87 (s, 9H), 0.15 (s, 3H), 0.09 (s, 3H), 0.05 (s,3H), 0.04 (s, 3H).

MS (ESI) m/z: 749 (M+23)⁺.

R_(f)=0.25 (Hex:EtOAc, 4:1).

Example 18 Compound 12g

To a solution of 12f (438 mg, 0.6 mmol) in CH₂Cl₂ (10 mL) was added Et₃N(1.67 mL, 12 mmol), DMAP (74 mg, 0.6 mmol) and Ac₂O (567 μL, 6 mmol) at0° C. The reaction mixture was stirred at 23° C. for 12 h. Then, thereaction was extracted with HCl 0.1N (10 mL) and the organic layer wasdried over Na₂SO₄, filtered, and concentrated under reduced pressure.The residue was purified by flash column chromatography on silica gel(Hex:EtOAc 7:1) to obtain compound 12g (343 mg, 74%) as a colourlessoil. ¹H NMR (300 MHz, CDCl₃) δ 7.23 (d, J=8.1 Hz, 2H), 6.87 (d, J=8.7Hz, 2H), 5.74 (dt, J=19.8, 9.9 Hz, 1H), 5.52-5.49 (m, 1H), 5.13-5.07 (m,2H), 4.65 (s, 2H), 4.42 (dd, J=13.5, 12.0 Hz, 2H), 3.80 (s, 3H),3.66-3.62 (m, 2H), 3.60-3.57 (m, 1H), 3.54-3.47 (m, 4H), 3.40-3.34 (m,1H), 3.38 (s, 3H), 3.28 (d, J=5.7 Hz, 1H), 2.81-2.76 (m, 1H), 2.48 (d,J=8.7 Hz, 1H), 1.97 (s, 3H), 1.83-1.73 (m, 1H), 1.56 (bs, 1H), 1.31 (s,3H), 1.07 (d, J=6.9 Hz, 3H), 0.91 (s, 9H), 0.88 (s, 9H), 0.12 (s,3H),0.06 (s, 3H), 0.03 (s, 6H).

MS (ESI) m/z: 791 (M+23)⁺.

R_(f)=0.26 (Hex:EtOAc, 4:1).

Example 19 Compound 12h

To a solution of 11a (75 mg, 0.117 mmol) in CH₂Cl₂ (3 mL) was addedDIPEA (82 μL, 0.47 mmol) and TESCl (40 μL, 0.234 mmol) at 0° C. Thereaction mixture was stirred at 23° C. for 3 h. Then, 0.1N HCl was addeduntil pH=4-5, and the reaction was extracted with CH₂Cl₂ (2×10 mL). Thecombined organic layers were dried over Na₂SO₄, filtered, andconcentrated under reduced pressure. The residue was purified by flashcolumn chromatography on silica gel (Hex:EtOAc, 12:1) to obtain compound12h (77 mg, 87%) as a pale yellow oil.

¹H NMR (300 MHz, CDCl₃) δ 7.22 (d, J=8.4 Hz, 2H), 6.87 (d, J=8.4 Hz,2H), 5.94-5.82 (m, 1H), 5.11 (dd, J=9.9, 2.1 Hz, 1H), 5.08 (dd, J=16.8,2.1 Hz, 1H), 4.41(dd, J=17.1, 11.7 Hz, 2H), 4.33-4.29 (m, 1H), 3.87(dd,1H), 3.80 (s, 3H), 3.65-3.60 (m, 2H), 3.49 (dd, J=9.9, 5.1 Hz, 1H),3.33 (d, J=6.9 Hz, 2H), 3.24 (d, J=4.5 Hz, 1H), 2.56 (d, J=9.3 Hz, 1H),2.30-2.25 (m, 1H), 1.82-1.75 (m, 2H), 1.31 (s, 3H), 1.03 (d, J=6.6 Hz,3H), 0.93-0.90 (m, 9H), 0.92 (s, 9H), 0.87 (s, 9H), 0.57 (q, J=7.8 Hz,6H), 0.16 (s, 3H), 0.10 (s, 3H), 0.07 (s, 3H), 0.05 (s, 3H).

MS (ESI) m/z: 775 (M+23)⁺.

R_(f)=0.58 (Hex:EtOAc, 4:1).

Example 20 Compound 12i

To a solution of 11a (128 mg, 0.2 mmol) in CH₂Cl₂ (10 mL) was addedDIPEA (104 μL, 0.6 mmol), DMAP (2 mg, 0.02 mmol) and SEMCl (53 μL, 0.3mmol) at 23° C. The reaction mixture was stirred at 23° C. for 6 h.Then, 0.1N HCl was added until pH=4-5, and the reaction was extractedwith CH₂Cl₂ (2×20 mL). The combined organic layers were dried overNa₂SO₄, filtered, and concentrated under reduced pressure. The residuewas purified by flash column chromatography on silica gel (Hex:EtOAc,10:1) to obtain compound 12i (142 mg, 92%) as a pale yellow oil.

¹H NMR (300 MHz, CDCl₃) δ 7.22 (d, J=8.5 Hz, 2H), 6,86 (d, J=8.5 Hz,2H), 5.79-5.88 (m, 1H), 5.10-5.17 (m, 2H), 4.61 (s, 2H), 4.42 (dd,J=15.9, 11.5 Hz, 2H), 4.17-4.22 (m, 1H), 3.76-3.87 (m, 1H), 3.79 (s,3H), 3.42-3.62 (m, 3H), 3.36 (d, J=6.8 Hz, 1H), 2.56 (d, J=9.3 Hz, 1H),2.40-2.45 (m, 1H), 1.72-1.83 (m, 2H), 1.25 (s, 3H), 1.06 (d, J=6.6 Hz,3H), 0.91 (s, 9H), 0.87 (s, 9H), 0.15 (s, 3H), 0.09 (s, 3H), 0.05 (s,3H), 0.04 (s, 3H), 0.00 (s, 9H).

¹³C-NMR (75 MHz, CDCl3): d 159.4, 137.8, 130.4, 129.3, 117.4, 114.0,95.2, 73.1, 72.8, 70.3, 69.4, 65.3, 64.8, 64.2, 60.6, 55.4, 49.2, 47.0,33.8, 29.9, 26.3, 26.0, 18.5, 18.3, 18.1, 15.1, 13.7, −1.2, −4.2, −5.1,−5.2.

MS (ESI) m/z: 792 (M+23)⁺.

R_(f)=0.56 (Hex:EtOAc, 4:1).

Example 21 Compound 12j

To a solution of 11a (600 mg, 0.93 mmol) in CH₂Cl₂ (10 mL) was addedEt₃N (2.61 mL, 18.76 mmol), DMAP (115 mg, 0.93 mmol) and Ac₂O (887 μL,9.39 mmol) at 0° C. The reaction mixture was stirred at 23° C. for 3 h.Then, 0.1N HCl was added until pH=4-5, and the reaction was extractedwith CH₂Cl₂ (2×20 mL). The combined organic layers were dried overNa₂SO₄, filtered, and concentrated under reduced pressure. The residuewas purified by flash column chromatography on silica gel (Hex:EtOAc,from 10:1 to 5:1) to obtain compound 12j (592 mg, 87%) as a pale yellowoil.

¹H NMR (300 MHz, CDCl₃) δ 7.22 (d, J=8.7 Hz, 2H), 6.87 (d, J=8.7 Hz,2H), 5.72-5.60 (m, 1H), 5.53-5.50 (m, 1H), 5.16-5.07 (m, 2H), 4.42 (s,2H), 4.03 (dd, 11.1, 6.3 Hz, 1H), 3.90 (dd, J=11.1, 6.9 Hz, 1H), 3.80(s, 3H), 3.58 (dd, J=10.2, 5.7 Hz, 1H), 3.47 (dd, J=10.2, 6.3 Hz, 1H),3.38-3.34 (m, 3H), 2.88-2.83 (m, 1H), 2.48 (d, J=9.3 Hz, 1H), 2.01 (s,3H), 1.98 (s, 3H), 1.95-1.90 (m, 1H), 1.83-1.74 (m, 1H), 1.323 (s, 3H),1.06 (d, J=6.6 Hz, 3H), 0.88 (s, 9H), 0.87 (s, 9H), 0.12 (s, 3H), 0.06(s, 3H), 0.03 (s, 3H), 0.02 (s, 3H).

MS (ESI) m/z: 745 (M+23)⁺.

R_(f)=0.34 (Hex:EtOAc, 4:1).

Example 22 Compound 12k

To a solution of crude 12e (545 mg, 0.73 mmol) in a mixture ofCH₂Cl₂:H₂O (8:0.4 mL) was added2,3-dichloro-5,6-dicyano-1,4-benzoquinone (329 mg, 1.45 mmol) at 23° C.The reaction mixture was stirred at 23° C. for 45 min. Saturated aqueoussolution of NaHCO₃ (30 mL) was added and the mixture was extracted withCH₂Cl₂ (3×40 mL). The combined organic layers were dried over Na₂SO₄,filtered, and concentrated under reduced pressure. The residue wassolved in MeOH and NaBH₄ (70 mg, 1.9 mmol) was added. The mixture wasstirred at 23° C. for 2 h and then, the reaction was concentrated underreduced pressure. A saturated aqueous solution of NaHCO₃ (20 mL) wasadded and the mixture was extracted with CH₂Cl₂ (3×30 mL). The combinedorganic layers were dried over Na₂SO₄, filtered, and concentrated underreduced pressure. The residue was purified by flash columnchromatography on silica gel (Hex:EtOAc, 10:1) to obtain 12k (300 mg,65%) as a pale yellow oil.

¹H NMR (300 MHz, CDCl₃) δ 5.88-5.80 (m, 1H), 5.15-5.09 (m, 2H),4.18.4.17 (m, 1H), 3.92 (dd, J=10.5, 4.5 Hz, 1H), 3.86-3.68 (m, 1H),3.66-3.56 (m, 3H), 3.50-3.47 (m, 1H), 3.33 (d, J=3.9, 1H), 2.54 (d,J=9.3 Hz, 1H), 2.38-2.34 (m, 1H), 1.87-1.86 (m, 1H), 1.71-1.62 (m, 1H),1.33 (s, 3H), 1.03 (d, J=6.9 Hz, 3H), 0.95 (t, J=8.1 Hz, 9H), 0.87 (s,9H), 0.87 (s, 9H), 0.67 (q, J=8.4 Hz, 6H), 0.05 (s, 3H), 0.04 (s, 3H),0.03 (s, 3H), 0.02 (s, 3H).

MS (ESI) m/z: 655 (M+23)⁺, 633 (M+1)⁺.

R_(f)=0.38 (Hex:EtOAc, 4:1).

Example 23 Compound 12l

To a solution of 12e (100 mg, 0.13 mmol) in CH₂Cl₂ (6 mL) was addedDess-Martin periodinane (113 mg, 0.26 mmol) and catalytic amount ofNaHCO₃ at 23° C. The reaction mixture was stirred at 23° C. for 2 h.Saturated aqueous solution of NaHCO₃ (10 mL) was added and the mixturewas extracted with CH₂Cl₂ (3×10 mL). The combined organic layers weredried over Na₂SO₄, filtered, and concentrated under reduced pressure.The residue was purified by flash column chromatography on silica gel(Hex:EtOAc, 20:1) to obtain 12l (110 mg, 96%) as apale yellow oil.

¹H NMR (300 MHz, CDCl₃) δ 7.27 (d, J=8.7 Hz, 2H), 6.90 (d, J=8.7 Hz,2H), 5.78 (ddd, J=16.8, 10.2, 9.0 Hz, 1H), 5.29-5.22 (m, 2H), 4.43 (q,J=11.4 Hz, 2H), 4.04 (dd, J=10.2, 4.2 Hz, 1H), 3.84 (s, 3H), 3.77-3.72(m, 1H), 3.66-3.60 (m, 2H), 3.45-3.30 (m, 5H), 2.50 (d, J=9.3 Hz, 1H),1.85-1.75 (m, 1H), 1.32 (s, 3H), 1.09 (d, J=6.6 Hz, 1H), 0.95 (t, J=7.8Hz, 9H), 0.91 (s, 9H), 0.87 (s, 9H), 0.63 (q, J=7.8 Hz, 6H), 0.08 (s,3H), 0.07 (s, 3H), 0.01 (s, 3H), 0.00 (s, 3H).

¹³C NMR (75 MHz, CDCl₃) δ 209.9, 159.1, 134.3, 130.2, 129.0, 119.3,113.7, 78.0, 72.3, 72.1, 64.8, 63.0, 62.6, 62.3, 61.1, 56.1, 55.2, 33.6,29.7, 25.9, 25.8, 18.2, 18.1, 15.1, 11.9, 6.8, 4.6, −5.3, −5.4, −5.5.

MS (ESI) m/z: 773 (M+23)⁺.

R_(f)=0.57 (Hex:EtOAc, 4:1).

Example 24 Compound 12m

To a solution of 12k (280 mg, 0.44 mmol) in THF (5 mL) was added E₃N(368 μL, 2.64 mmol), DMAP (5 mg, 0.04 mmol) and Ac₂O (125 μL, 1.32 mmol)at 0° C. The reaction mixture was stirred at 23° C. for 1 h. Then, 0.1NHCl was added until pH=4-5, and the reaction was extracted with CH₂Cl₂(2×10 mL). The combined organic layers were dried over Na₂SO₄, filtered,and concentrated under reduced pressure. The residue was purified byflash column chromatography on silica gel (Hex:EtOAc, 15:1) to obtaincompound 12m (258 mg, 87%) as a pale yellow oil.

¹H NMR (300 MHz, CDCl₃) δ 5.90 (ddd, J=17.1, 10.8, 9.6 Hz, 1H),5.16-5.09 (m, 2H), 4.32-4.28 (m, 1H), 4.09 (dd, J=11.1, 5.7 Hz, 1H),3.89-3.76 (m, 3H), 3.70-3.67 (m, 2H), 3.56 (dd, J=9.9, 5.1 Hz, 1H),3.08, (d, J=4.5 Hz, 1H), 2.57 (d, J=9.3 Hz, 1H), 2.40-2.31 (m, 1H), 2.05(s, 3H), 1.30 (s, 3H), 1.10 (d, J=6.9 Hz, 3H), 0.96 (t, J=8.1 Hz, 9H),0.88 (s, 9H), 0.87 (s, 9H), 0.69 (q, J=8.1 Hz, 6H), 0.05 (s, 3H), 0.03(s, 6H), 0.02 (s, 3H).

R_(f)=0.66 (Hex:EtOAc, 4:1).

Example 25 Compound 12n

To a solution of 11a (110 mg, 0.17 mmol) in CH₂Cl₂ (5 mL) was addedPhB(OH)₂ (33 mg, 0.26 mmol) and the reaction mixture was stirred at 23°C. for 1 h. Then, the solution was filtered through a pad of celite. Thefiltrate was dried over Na₂SO₄, filtered, and concentrated under reducedpressure. The residue was purified by flash column chromatography onsilica gel (Hex:EtOAc, from 20:1 to 10:1) to obtain compound 12n (94 mg,75%) as a pale yellow oil.

¹H NMR (300 MHz, CDCl₃) δ 7.81 (dd, J=7.8, 1.2 Hz, 2H), 7.65-7.60 (m,1H), 7.56-7.42 (m, 2H), 7.24 (d, J=8.7 Hz, 2H), 6.83 (d, J=8.7 Hz, 2Hz), 5.88 (ddd, J=18.9, 10.2, 8.7 Hz, 1H), 5.23-5.17 (m, 2 H), 4.54 (dd,J=6.6, 2.4 Hz, 1H), 4.39 (dd, J=18.0, 11.1 Hz, 2H), 4.27 (dd, J=11.1,3.3 Hz, 1H), 4.03 (brd, J=0.5 Hz, 1H), 3.97 (dd, J=10.2, 6.3 Hz, 1H),3.82 (d, J=5.1 Hz, 1H), 3.68 (s, 3H), 3.65 (dd, J=10.5, 3.6 Hz, 1H),3.46-3.35 (m, 2H), 2.87 (brd, J=8.4 Hz, 1H), 2.70 (d, J=9.3 Hz, 1H),1.93-1.83 (m, 2H), 1.30 (s, 3H), 1.11 (d, J=6.6 Hz, 3H), 0.95 (s, 9H),0.92 (s, 9H), 0.18 (s, 3H), 0.14 (s, 3H), 0.08 (s, 3H), 0,07 (s, 3H).

R_(f)=0.46 (Hex:EtOAc, 4:1).

Example 26 Compound 12o

The title compound was obtained as precursor of 11a in the reductionreaction of 10a before the treatment with H₂O₂.¹H NMR (300 MHz, CDCl₃) δ7.20 (d, J=8.4 Hz, 2H), 6.85 (d, J=8.4 Hz, 2H), 5.87-5.79 (m, 1H),5.22-5.17 (m, 2H), 4.38 (dd, J=10.8 Hz, 13.2 Hz, 2H), 4.30 (dd J=6.6,2.7 Hz, 1H), 4.07 (dd, J=10.8, 3.0 Hz, 1H), 3.83-3.72 (m, 2H), 3.80 (s,3H), 3.69 (d, J=5.1 Hz, 1H), 3.50 (dd, J=9.9, 3.0 Hz, 1H), 3.37-3.32 (m,2H), 2.67 (brd, J=8.4 Hz, 1H), 2.62 (d, J=9.3 Hz, 1H), 1.81-1.76 (m,2H), 1.21 (s, 3H), 1.06 (d, J=6.9 Hz, 3H), 0.91 (s, 9H), 0.89 (s, 9H),0.12 (s, 3H), 0.05 (s, 3H), 0.03 (s, 3H), 0.02 (s, 3H).

¹³C NMR (75 MHz, CDCl₃) δ 159.1, 134.0, 130.2, 129.1, 118.4, 113.7,76.2, 72.9, 70.0, 67.1, 64.8, 59.5, 55.2, 45.7, 43.9, 33.4, 26.4, 26.0,25.9, 25.5, 18.2, 14.9, 14.0, 13.3, −4.3, −4.9, −5.3, −5.4.

MS (ESI) m/z: 661 (M+23)⁺.

R_(f)=0.50 (Hex:EtOAc, 4:1).

Example 27 Compound 12p

To a solution of 11a (119 mg, 0.18 mmol) in THF (10 mL) was added CDI(49 mg, 0.3 mmol) and NaH (8 mg, 0.2 mmol) and the reaction mixture wasstirred at 23° C. for 3 h. Then, a saturated aqueous solution of NaHCO₃(10 mL) was added and the mixture was extracted with CH₂Cl₂ (3×10 mL).The combined organic layers were dried over Na₂SO₄, filtered, andconcentrated under reduced pressure. The residue was purified by flashcolumn chromatography on silica gel (Hex:EtOAc, 5:1) to obtain 12p (97mg, 78%) as a pale yellow oil.

¹H NMR (300 MHz, CDCl₃) δ 7.19 (d, J=8.4 Hz, 2H), 6.87 (d, J=8.4 Hz,2H), 5.79-5.70 (m, 1H), 5.32-5.26 (m, 2H), 4.67 (dd, J=7.5, 2.4 Hz, 1H),4.43 (dd, J=10.5, 3.6 Hz, 1H), 4.35 (q, J=10.2 Hz, 2H), 4.25 (dd,J=16.2, 15.3 Hz, 2H), 3.80 (s, 3H), 3.77-3.69 (m, 2H), 3.54 (dd, J=10.5,3.0 Hz, 1H), 3.42 (dd, J=9.3, 4.8 Hz, 1H), 3.30 (t, J=9.3 Hz, 1H), 2.92(br d, J=8.4 Hz, 1H), 2.66 (d, J=9.6 Hz, 1H), 1.95-1.92 (m, 1H), 1.21(s, 3H), 1.05 (d, J=6.9 Hz, 3H), 0.89 (s, 9H), 0.88 (s, 9H), 0.11 (s,3H), 0.07 (s, 6H), 0.05 (s, 3H).

¹³C NMR (75 MHz, CDCl₃) δ 173.8, 159.4, 154.1, 130.5, 129.4, 114.0,99.3, 76.5, 73.0, 72.6, 68.0, 66.0, 64.7, 64.6, 63.6, 61.2, 59.5, 58.8,55.4, 44.5, 42.1, 41.6, 33.7, 29.7, 28.8, 26.3, 26.3, 26.2, 26.1, 19.0,18.6, 18.3, 18.2, 15.2, 14.9, 13.7, −4.1, −4.2, −5.1, −5.2.

MS (ESI) m/z: 687 (M+23)⁺.

R_(f)=0.47 (Hex:EtOAc, 4:1).

Example 28 Compound 12q

The title compound was obtained as precursor of 11b in the reductionreaction of 10b before the treatment with H₂O₂. ¹H NMR (300 MHz, CDCl₃)δ 7.16 (d, J=8.4 Hz, 2H), 6.82 (d, J=8.7 Hz, 2H), 5.86-5.74 (m, 1H),5.20-5.15 (m, 2H), 4.40-4.34 (m, 2H), 4.18-4.15 (m, 1H), 4.09-4.03 (m,1H), 3.85-3.79 (m, 1H), 3.76 (s, 3H), 3.66 (d, J=7.8 Hz, 1H), 3.58 (q,J=7.2 Hz, 1H), 3.47 (dd, J=9.9, 2.4 Hz, 1 H), 3.37-3.27 (m, 1H), 2.87(br d, J=8.7 Hz, 1H), 2.74 (q, J=7.5 Hz, 1H), 2.63 (d, J=9.3 Hz, 1H),1.72-1.65 (m, 2H), 1.18 (s, 3H), 1.03 (d, J=6.3 Hz, 3H), 0.91-0.85 (m,9H), 0.84 (s, 9H), 0.60 (q, J=7.8 Hz, 6H), −0.01 (s, 3H), −0.02 (s, 3H).

R_(f)=0.65 (Hex:EtOAc, 4:1).

Example 29 Compound 13a

Over a solution of 12a (5.91 g, 7.85 mmol) in CH₂Cl₂ (80 mL) was bubbleda current of O₃ during 15 min at −78° C. Then, Ph₃P (6.29 g, 24 mmol)was added and the mixture was allowed to warm to room temperature, andthe stirring was continued for 12 h. The mixture was concentrated underreduced pressure and the residue was purified by flash columnchromatography on silica gel (Hex:EtOAc, 20:1) to afford compound 13a(4.99 g, 84%) as a white solid. ¹H NMR (300 MHz, CDCl₃) δ 9.80 (d, J=3.0Hz, 1H), 7.20 (d, J=8.7 Hz, 2H), 6.85 (d, J=8.7 Hz, 2H), 4.66 (m, 1H),0.439 (s, 2H), 3.84 (m, 2H), 3.78 (s, 3H), 3.68 (m, 2H), 3.61 (m, 2H),3.37 (m, 2H), 2.58 (d, J=9.0 Hz, 1H), 2.44 (m, 1H), 1.82 (m, 1H), 1.72(m, 1H), 1.29 (s, 3H), 1.05 (d, J=6.6 Hz, 3H), 0.91 (s, 9H), 0.87 (s,9H), 0.85 (s, 9H), 0.15 (s, 3H), 0.11 (s, 3H), 0.06 (s, 6H), 0.00 (s,6H).

¹³C NMR (75 MHz, CDCl₃) δ 205.3, 159.2, 130.0, 129.0, 113.7, 76.4, 72.8,72.7, 67.9, 64.6, 63.9, 60.8, 60.1, 57.7, 55.1, 44.4, 33.5, 26.1, 25.7,18.3, 18.1, 17.8, 14.8, 12.9, −4.6, −5.3, −5.5, −5.5, −5.7, −5.7.

[α]²⁵ _(D) +2.3 (c 0.50, CH₂Cl₂).

R_(f)=0.46 (Hex:EtOAc, 4:1).

Example 30 Compound 13b

To a solution of 12c (2.25 g, 2.84 mmol) in THF:H₂O (70:30, 105 mL) wasadded NMO (1.16 g, 9.94 mmol) and OsO₄ (5.68 mL, 0.568 mmol, 0.1 M in^(t)BuOH) at 23° C. and the reaction mixture was stirred at 23° C.overnight. Florisil (16 g), NaHSO₃ (16 g), and EtOAc (160 mL) were addedand the mixture was stirred vigorously during 30 min. The mixture wasfiltered through a pad of Celite, and the filtrate was concentrated toprovide the corresponding diol. This diol was dissolved in anhydrousToluene (50 mL) and Pb(OAc)₄ (1.57 g, 3.55 mmol) was added at 0° C.,stirred for 30 min, filtered through a pad of Celite, washed with EtOAcand concentrated under reduced pressure. The residue was purified byflash column chromatography on silica gel (Hex:EtOAc, 20:1) to affordcompound 13b (0.97 g, 43%) as a colourless oil.

¹H NMR (300 MHz, CDCl₃) δ 9.61 (d, J=3.9 Hz, 1H), 7.22 (d, J=8.5 Hz,2H), 6.87 (d, J=8.5 Hz, 2H), 5.56 (dd, J=10.3, 6.6 Hz, 1H), 4.42 (s,2H), 3.95 (m, 1H), 3.80 (s, 3H), 3.54 (m, 2H), 3.38 (d, J=7.0 Hz, 2H),3.24 (d, J=6.8 Hz, 1H), 3.04 (m, 1H), 2.49 (d, J=9.0 Hz, 1H), 1.98 (s,3H), 1.79 (m, 1H), 1.31 (s, 3H), 1.06 (d, J=6.8 Hz, 3H), 0.92 (s, 9H),0.88 (s, 9H), 0.85 (s, 9H), 0.13 (s, 3H), 0.06 (s, 6H), 0.04 (s, 3H),0.03 (s, 6H).

¹³C NMR (75 MHz, CDCl₃) δ 203.3, 170.1, 159.4, 130.4, 129.3, 114.0,76.6, 73.1, 72.7, 69.1, 64.4, 63.9, 61.3, 60.0, 58.4, 55.4, 46.4, 33.4,29.9, 26.4, 26.1, 26.0, 21.2, 18.6, 18.4, .18.3, 15.1, 12.8, −4.1, −5.0,−5.1, −5.2, −5.3, −5.4.

MS (ESI) m/z: 819 (M+23)⁺.

R_(f)=0.47 (Hex:EtOAc, 4:1).

Example 31 Compound 13c

To a solution of 13a (90 mg, 0.12 mmol) in CH₂Cl₂ (10 mL) was added Py(0.19 mL, 2.4 mmol), DMAP (22 mg, 0.18 mmol) and (CF₃CO)₂O (0.17 mL, 1.2mmol) at 0° C. and the reaction mixture was stirred at 0° C. for 2 h.Then, the reaction was concentrated under reduced pressure to obtain 13cwhich was used in subsequent steps with no further purification. ¹H NMR(300 MHz, CDCl₃) δ 9.63 (d, J=2.4 Hz, 1H), 7.19 (d, J=8.6 Hz, 2H), 6.85(d, J=8.6 Hz, 2H), 5.75-5.79 (m, 1H), 4.34-4.42 (m, 2H), 3.86-3.90 (m,2H), 3.78 (s, 3H), 3.48 (d, J=5.4 Hz, 1H), 3.30-3.38 (m, 3H), 3.08-3.13(m, 1H), 2.51 (d, J=9.0 Hz, 1H), 2.21-2.27 (m, 1H), 1.77-1.82 (m, 1H),1.25 (s, 3H), 1.05 (d, J=6.8 Hz, 3H), 0.91 (s, 9H), 0.86 (s, 9H), 0.85(s, 9H), 0.13 (s, 3H), 0.07 (s, 3H), 0.06 (s, 3H), 0.02 (s, 6H), 0.00(s, 3H).

R_(f)=0.70 (Hex:EtOAc, 4:1).

Example 32 Compound 13d

Following the procedure described in example 29, 12h (1 g, 1.32 mol) wasconverted to 13d (715 mg, 72%, colourless oil) after purification of thecrude product by flash column chromatography (Hex:EtOAc, 20: 1).

¹H NMR (300 MHz, CDCl₃) δ 9.81 (d, J=3.0 Hz, 1H), 7.21 (d, J=8.7 Hz,2H), 6.86 (d, J=8.4 Hz, 2H), 4.70-4.64 (m, 1H), 4.40 (s, 2H), 3.89-3.81(m, 1H), 3.80 (s, 3H), 3.75-3.66 (m, 2H), 3.64 (d, J=6.6 Hz, 2H),3.38-3.35 (m, 2H), 2.60 (d, J=9.3 Hz, 1H), 2.50-2.46 (m, 1H), 1.85-1.80(m, 1H), 1.77-1.68 (m, 1H), 1.29 (s, 3H), 1.06 (d, J=6.6 Hz, 3H),0.94-087 (m, 9H), 0.92 (s, 9H1), 0.87 (s, 9H), 0.55 (q, J=7.8 Hz, 6H),0.16 (s, 3H), 0.11 (s, 3H), 0.07 (s, 3H), 0.06 (s, 3H).

MS (ESI) n/z: 777 (M+23)⁺.

R_(f)=0.5 (Hex:EtOAc, 4:1).

Example 33 Compound 13e

Following the procedure described in example 29, 12j (590 mg, 0.81 mol)was converted to 13e (420 mg, 71%, pale yellow, oil) after purificationof the crude product by flash column chromatography (Hex:EtOAc, 10:1).

¹H NMR (300 MHz, CDCl₃) δ 9.58 (d, J=20.0 Hz, 1H), 7.19 (d, J=8.4 Hz,2H), 6.82 (d, J=8.4 Hz, 2H), 5.58 (dd, J=5.1, 4.6 Hz, 1H), 4.38 (s, 2H),4.30-4.23 (m, 2H), 3.76 (s, 3H), 3.50 (dd, J=6.9, 5.1 Hz, 2H), 3.30 (d,J=7.0 Hz, 2H), 3.25-3.22 (m, 2H), 2.44 (d, J=9.3 Hz, 1H), 2.15-2.12 (m,1H), 1.93 (s, 3H), 1.92 (s, 3H), 1.23 (s, 3H), 1.12 (d, J=6.6 Hz, 3H),0.84 (s, 9H), 0.82 (s, 9H), 0.09 (s, 3H), 0.02 (s, 3H), 0.01 (s, 3H),0.00 (s, 3H).

R_(f)=0.26 (Hex:EtOAc, 4:1).

Example 34 Compound 13f

Following the procedure described in example 29, 12g (342 mg, 0.44 mol)was converted to 13f (306 mg, 90%, pale yellow oil) after purificationof the crude product by flash column chromatography (Hex:EtOAc from 4:1to 0:1).

¹H NMR (300 MHz, CDCl₃) δ 9.64 (d, J=3.3 Hz, 1H), 7.22 (d, J=8.1 Hz,2H), 6.86 (d, J=8.4 Hz, 2H), 5.64 (dd, J=6.6, 3.9 Hz, 1H), 4.63 (s, 2H),4.40 (s, 2H), 3.86 (dd, J=9.9, 7.5 Hz, 1H), 3.79 (s, 3H), 3.74 (dd,J=10.2, 4.5 Hz, 1H), 3.65-3.61 (m, 2H), 3.53-3.50 (m, 4H), 3.85-3.34 (m,1H), 3.37 (s, 3H), 3.21 (d, J=7.2 Hz, 1H), 3.15-3.13 (m, 1H), 2.48 (d,J=9.0 Hz, 1H), 1.98 (s, 3H), 1.80-1.75 (m, 1H), 1.28 (s, 3H), 1.05 (d,J=6.9 Hz, 3H), 0.90 (s, 9H), 0.87 (s, 9H), 0.11 (s, 3H), 0.05 (s, 3H),0.04 (s, 3H), 0.03 (s, 3H).

MS (ESI) m/z: 793 (M+23)⁺.

R_(f)=0.1 (Hex:EtOAc, 4:1).

Example 35 Compound 13g

Following the procedure described in example 29, 12m (200 mg, 0.3 mmol)was converted to 13g (173 mg, 86%, pale yellow oil) after purificationof the crude product by flash column chromatography (Hex:EtOAc, 15:1).

¹H NMR (300 MHz, CDCl₃) δ 9.84 (d, J=2.7 Hz, 1H), 4.67-4.61 (m, 1H),4.08 (dd, J=11.1, 5.7 Hz, 1H), 3.95-3.84 (m, 3H), 3.81 (d, J=5.1 Hz,2H), 3.70 (d, J=6.9 Hz, 1H), 3.47 (d, J=5.4 Hz, 1H), 2.64-2.61 (m, 1H),2.26 (d, J=9.3 Hz, 1H), 2.04 (s, 3H), 1.85-1.80 (m, 1H), 1.30 (s, 3H),1.11 (d, J=6.6 Hz, 3H), 0.96 (t, J=8.1 Hz, 9H), 0.87 (s, 9H), 0.85 (s,9H), 0.68 (q, J=8.1 Hz, 6H), 0.07 (s, 3H), 0.06 (s, 3H), 0.03 (s, 6H).

MS (ESI) m/z: 699 (M+23)⁺, 677 (M+1)⁺.

R_(f)=0.52 (Hex:EtOAc, 4:1).

Example 36 Compounds 14a and 14b

To a solution of N-methoxy-N-methylacetamide (0.8 mL g, 7.56 mmol) inTHF (2 mL) at −78° C. was added bis-(trimethylsilyl)-lithiumamide (7.56mL, 1.0 M in THF, 7.56 mmol) and the reaction mixture was stirred for 1h at −78° C. Then, a solution of 13a (1.61 g, 2.13 mmol) in THE (10 mL)was added over the previous solution and the reaction mixture wasstirred for an additional 1 h at −78° C. Then, a saturated aqueoussolution of NH₄Cl (50 mL) was added and the reaction was extracted withEtOAc (3×60 mL). The combined organic layers were dried over Na₂SO₄,filtered, and concentrated under reduced pressure. The residue waspurified by flash column chromatography on silica gel (Hex:EtOAc from4:1 to 2:1) to yield 14a and 14b (25:75) as colourless oils (1.67 g, ina combined 91% of yield).

14a: ¹H NMR (300 MHz, CDCl₃) δ 7.20 (d, J=8.7 Hz, 2H), 6.85 (d, J=8.7Hz, 2H), 4.46-4.43 (m, 1H), 4.39 (s, 2H), 4.33 (m, 1H), 4.14 (d, J=7.2Hz, 1H), 3.92-3.88 (m, 2H), 3.83 (d, J=3.6 Hz, 1H), 3.78 (s, 3H), 3.63(s, 3H), 3.61-3.57 (m, 3H), 3.41-3.30 (m, 2H), 3.17 (s, 3H), 3.0-2.91(m, 1H), 2.63-2.62 (m, 1H), 2.58 (d, J=9.0 Hz, 1H), 2.02-1.96 (m, 1H),1.85-1.78 (m, 1H), 1.75-1.72 (m, 1H), 1.27 (s, 3H), 1.06 (d, J=6.6 Hz,3H), 0.91 (s, 9H), 0.86 (s, 18H), 0.14 (s, 3H), 0.11 (s, 3H), 0.08 (s,3H), 0.05 (s, 3H), 0.02 (s, 3H), 0.01 (s, 3H).

¹³C NMR (75 MHz, CDCl₃) δ 173.8, 159.4, 130.3, 129.3, 114.0, 76.3, 73.0,72.6, 70.4, 70.1, 64.8, 64.0, 61.9, 61.4, 60.6, 55.4, 47.9, 44.4, 36.9,34.0, 32.1, 29.9, 26.5, 26.4, 26.1, 26.0, 18.6, 18.3, 18.0, 15.3, 12.8,−4.3, −5.0, −5.1, −5.2, −5.4.

MS (ESI) m/z: 858 (+1)⁺.

[α]²⁵ _(D) −10.7 (c 0.5, CH₂Cl₂).

14b: ¹H NMR (300 MHz, CDCl₃) δ 7.17 (d, J=8.4 Hz, 2H), 6.83 (d, J=8.4Hz, 2H), 4.52-4.51 (m, 1H), 4.45 (s, 3H), 4.37 (s, 2H), 4.28-4.23 (m,1H), 3.91-3.88 (m, 1H), 3.81 (m, 1H), 3.76 (s, 3H), 3.64 (s, 3H),3.61-3.52 (m, 3H), 3.48-3.43 (dd, J=10.5, 3.3 Hz, 1H), 3.38-3.35 (m,2H), 3.15 (s, 3H), 2.84-2.79 (m, 1H), 2.57 (d, J=9.0 Hz, 1H), 1.94-1.92(m, 1H), 1.83-1.81 (m, 1H), 1.72-1.69 (m, 1H), 1.24 (s, 3H), 1.05 (d,J=6.3 Hz, 3H), 0.89 (s, 9H), 0.86 (s, 9H), 0.85 (s, 9H), 0.13 (s, 3H),0.08 (s, 3H), 0.07 (s, 3H), 0.04 (s, 3H), 0.01 (s, 3H), −0.01 (s, 3H).

¹³C NMR (75 MHz, CDCl₃) δ 174.8, 159.4, 130.3, 129.2, 113.9, 76.4, 73.0,72.8, 69.2, 68.5, 64.9, 64.1, 61.4, 60.8, 60.1, 55.4, 47.8, 43.7, 34.1,26.5, 26.3, 26.2, 26.1, 26.0, 25.9, 18.7, 18.2, 17.9, 15.2, 12.7, −4.6,−4.9, −5.0, −5.2, −5.4, −5.5.

MS (ESI) m/z: 880 (M+23)⁺, 858 (M+1)⁺.

[α]²⁵ _(D) +12.8 (c 0.50, CH₂Cl₂).

R_(f)=0.44 (Hex:EtOAc, 2:1).

Example 37 Compounds 14c and 14d

To a solution of benzyl acetate (38 μL, 0.53 mmol) in dry THF (5 mL) at−78° C. was added lithium bis(trimethylsilyl)amide (264 μL, 1.0 M inTHF, 0.264 mmol) and the reaction mixture was stirred for 1 h at −78° C.Then, a solution of 13a (150 mg, 0.17 mmol) in THF (5 mL) was added overthe previous solution and the reaction mixture was stirred for 5 h at−78° C. Then, a saturated aqueous solution of NH4Cl (30 mL) was addedand the crude reaction was extracted with EtOAc (3×50 mL). The combinedorganic layers were dried over Na₂SO₄, filtered and concentrated invacuo. The residue was purified by flash column chromatography on silicagel (Hex:EtOAc from 20:1 to 5:1) to yield 14c (34 mg, 20%) and 14d (77mg, 44%) as colourless oils.

14c: ¹H NMR (300 MHz, CDCl₃) δ 7.28-7.39 (m, 5H), 7.19 (d, J=8.7 Hz,2H), 6.82 (d, J=8.7 Hz, 2H), 5.20 (s, 2H), 5.17 (s, 2H), 4.58-4.64 (m,1H), 4.38 (s, 2H), 3.78 (s, 3H), 3.58-3.82 (m, 4H), 3.50 (s, 2H),3.28-3.41 (m, 3H), 2.60 (dd, J=15.0 and 9.6 Hz, 1H), 2.53 (d, J=9.3 Hz,1H), 2.25 (dd, J=153, 4.7 Hz, 1H), 1.76-1.86 (m, 1H), 1.59-1.62 (m, 1H),1.26 (s, 3H), 1.05 (d, J=6.6 Hz, 3H), 0.91 (s, 9H), 0.88 (s, 9H), 0.17(s, 3H), 0.11 (s, 3H), 0.05 (s, 3H), 0.04 (s, 3H).

R_(f)=0.33 (Hex:EtOAc, 4:1).

14d: ¹H NMR (300 MHz, CDCl₃) δ 7.32-7.55 (m, 5H), 7.20 (d, J=8.7 Hz,2H), 6.84 (d, J=8.7 Hz, 2H), 5.19 (s, 2H), 4.43-4.48 (m, 1H), 4.40 (s,2H), 4.32-4.40 (m, 1H), 4.19-4.23 (m, 1H), 3.81 (s, 3H), 3.75-3.98 (m,3H), 3.42-3.64 (m, 3H), 3.39 (d, J=7.8 Hz, 2H), 2.60 (d, J=9.3 Hz, 1H),2.61-2.79 (m, 1H), 1.78-1.93 (m, 2H), 1.74-1.77 (m, 1H), 1.25 (s, H),1.05 (d, J=6.7 Hz, 3H), 0.92 (s, 9H), 0.88 (s, 9H), 0.82-0.92 (m, 6H),0.49-0.60 (m, 12H), 0.09 (s, 3H), 0.05 (s, 3H), 0.04 (s, 3H), 0.03 (s,3H).

MS (ESI) r/z: 927 (M+23)⁺.

R_(f)=0.30 (Hex:EtOAc, 4:1).

Example 38 Compound 15a

To a solution of 14a (1.09 g, 1.26 mmol) in CH₂Cl₂ (20 mL) was added2,6-lutidine (443 μL, 3.8 mmol) and TBSOTf (437 μL, 1.9 mmol) at 0° C.The reaction mixture was stirred at 0° C. for 40 min. Then, a saturatedaqueous solution of NH₄Cl (30 mL) was added, and the reaction wasextracted with CH₂Cl₂ (2×15 mL). The combined organic layers were driedover Na₂SO₄, filtered, and concentrated under reduced pressure. Theresidue was purified by flash column chromatography on silica gel(Hex:EtOAc, from 20:1 to 4:1) to obtain compound 15a (1.05 g, 85%) as apale yellow oil.

¹H NMR (300 MHz, CDCl₃) δ 7.23 (d, J=8.4 Hz, 2H), 6.87 (d, J=8.4 Hz,2H), 4.87-4.83 (m, 1H), 4.48-4.37 (m, 2H), 4.17-4.14 (m, 2H), 3.86 (dd,J=10.2, 7.0 Hz, 1H), 3.80 (s, 3H), 3.66 (s, 3H), 3.64-3.63 (m, 1H), 3.54(dd, J=10.2, 3.6 Hz, 1H), 3.53 (dd, J=9.0, 5.1 Hz, 1H), 3.35-3.29 (m,2H), 3.17 (s, 3H), 3.11-3.05 (m, 1H), 2.56-2.55 (m, 1H), 2.52 (d, J=8.1Hz, 1H), 2.31-2.28 (m, 1H), 1.84-1.82 (m, 1H), 1.81-1.78 (m, 1H), 1.29(s, 3H), 1.09 (d, J=6.6 Hz, 3H), 0.92 (s, 9H), 0.89 (s, 9H), 0.88 (s,9H), 0.87 (s, 9H), 0.15 (s, 6H), 0.1 (s, 3H), 0.09 (s, 3H), 0.06 (s,3H), 0.04 (s, 6H), 0.02 (s, 3H),

¹³C NMR (75 MHz, CDCl₃) δ 173.4, 159.4, 130.4, 129.4, 114.0, 76.0, 72.9,72.4, 69.5, 68.8, 64.6, 64.1, 61.4, 61.0, 59.3, 55.4, 50.1, 43.6, 34.3,29.9, 26.5, 26.2, 26.1, 26.0, 18.7, 18.3, 17.9, 15.4, 12.7, −4.4, −4.5,−4.6, −4.9, −5.0, −5.2, −5.4, −5.5.

MS (ESI) m/z: 994 (M+23)⁺, 972 (M+1)⁺.

[α²⁵ _(D) −20.0 (c 0.5, CH₂Cl₂).

R_(f)=0.43 (Hex:EtOAc, 4:1)

Example 39 Compound 15b

Following the procedure described in example 38, 14b (2.18 g, 2.52 mmol)was converted to 15b (2.02 g, 82%, white solid) after purification ofthe crude product by flash column chromatography (Hex:EtOAc 10:1).

¹H NMR (300 MHz, CDCl₃) δ 7.20 (d, J=8.7 Hz, 2H), 6.86 (d, J=8.7 Hz,2H), 4.85-4.82 (m, 1H), 4.44-4.35 (m, 2H), 4.09 (t, J=9.0 Hz, 1H), 3.80(s, 3H), 3.77-3.73 (m, 1H), 3.65 (s, 3H), 3.63-3.60 (m, 1H), 3.42-3.30(m, 3H), 3.15 (s, 3H), 2.75-2.72 (m, 1H), 2.61 (d, J=9.3 Hz, 1H), 2.48(dd, J=15.3, 2.1 Hz, 1H), 1.93-1.88 (m, 1H), 1.84-1.81 (m, 1H),1.77-1.74 (m, 1H), 1.27 (s, 3H), 1.08 (d, J=6.6 Hz, 3H), 0.90 (s, 3H),0.88 (s, 18H), 0.85 (s, 9H), 0.13, (s, 3H), 0.09 (s, 3H), 0.08 (s, 6H),0.04 (s, 3H), 0.03 (s, 3H), 0.01 (s, 6H).

¹³C NMR (75 MHz, CDCl₃) δ 173.3, 159.4, 130.4, 129.4, 114.0, 76.0, 72.9,69.5, 68.8, 64.6, 64.1, 61.3, 61.1, 59.3, 55.4, 50.1, 43.5, 34.3, 29.9,26.5, 26.2, 26.1, 26.0, 18.7, 18.3, 18.2, 17.9, 15.4, 12.7, −4.4, −4.5,−4.6, −4.9, −5.0.

MS (ESI) m/z: 994 (M+23)⁺, 972 (M+1)⁺.

[α]²⁵ _(D) +23.1 (c 0.50, CH₂Cl₂).

R_(f)=0.37 (Hex:EtOAc, 4:1).

Example 40 Compound 16a

To a solution of 15a (184 mg, 0.189 mmol) in CH₂Cl₂ (5 mL) was addedDess-Martin periodinane (325 mg, 0.76 mmol) and catalytic amount ofNaHCO₃ at 23° C. The reaction mixture was stirred at 23° C. for 3 h.Saturated aqueous solution of NaHCO₃ (20 mL) was added and the mixturewas extracted with CH₂Cl₂ (3×30 mL). The combined organic layers weredried over Na₂SO₄, filtered, and concentrated under reduced pressure.The residue was purified by flash column chromatography on silica gel(Hex:EtOAc, 10:1) to obtain 16a (150 mg, 81%) as a colourless oil.

¹H NMR (300 MHz, CDCl₃) δ 7.23 (d, J=8.7 Hz, 2H), 6.87 (d, J=8.7 Hz,2H), 4.72-4.67 (m, 1H), 4.43 (q, J=11.7 Hz, 2H), 3.80 (s, 3H), 3.78-3.77(m, 2H), 3.72-3.66 (m, 3H), 3.63 (s, 3H), 3.43-3.38 (m, 1H), 3.32-3.26(m, 3H), 3.15 (s, 3H), 2.72 (d, J=9.0 Hz, 1H), 2.65 (brd, J=8.7 Hz, 1H),2.59-2.51 (m, 1H), 1.79-1.72 (m, 1H), 1.32 (s, 3H), 1.06 (d, J=6.6 Hz,3H), 0.89 (s, 9H), 0.87 (s, 9H), 0.86 (s, 18H), 0.14 (s, 3H), 0.09 (s,3H), 0.06 (s, 3H), 0.05 (s, 6H), 0.04 (s, 3H), 0.00 (s, 6H).

¹³C NMR (75 MHz, CDCl₃) δ 210.7, 172.1, 159.1, 130.3, 129.0, 113.7,75.9, 72.6, 72.1, 68.1, 63.7, 63.3, 61.4, 61.1, 60.1, 59.9, 57.6, 55.1,37.2, 33.8, 29.7, 26.1, 26.0, 25.9, 25.8, 18.2, 18.1, 18.0, 15.2, 13.2,−4.3, −4.5, −4.7, −4.9, −5.2, −5.3, −5.4, −5.5.

MS (ESI) m/z: 993 (M+23)⁺.

[α]²⁵ _(D) −20.3 (c 0.50, CH₂Cl₂).

R_(f)=0.40 (Hex:EtOAc, 4:1).

Example 41 Compound 16b

To a solution of 15b (725 mg, 0.745 mmol) in CH₂Cl₂ (15 mL) was addedDess-Martin periodinane (1.26 g, 2.98 mmol) and catalytic amount ofNaHCO₃ at 23° C. The reaction mixture was stirred at 23° C. for 2 h. Asaturated aqueous solution of NaHCO₃ (30 mL) was added and the mixturewas extracted with CH₂Cl₂ (3×40 mL). The combined organic layers weredried over Na₂SO₄, filtered, and concentrated under reduced pressure.The residue (720 mg) was used in the next reaction without furtherpurification.

¹H NMR (300 MHz, CDCl₃) δ 7.21 (d, J=8.7 Hz, 2H), 6.83 (d, J=8.7 Hz,2H), 4.68-4.64 (m, 1H), 4.41 (q, J=11.7 Hz, 2H), 3.98-3.85 (m, 3H), 3.76(s, 3H), 3.67 (dd, J=9.9, 3.0 Hz, 1H), 3.63 (s, 3H), 3.58 (d, J=7.8 Hz,1H), 3.43 (dd, J=9.3, 6.9 Hz, 1H), 3.30-3.23 (m, 2H), 3.11 (s, 3H),3.93-2.88 (m, 1H), 2.62-2.57 (m, 2H), 2.55 (d, J=9.3 Hz, 1H), 1.75-1.70(m, 1H), 1.26 (s, 3H), 1.03 (d, J=6.6 Hz, 3H), 0.87 (s, 9H), 0.84 (s,9H), 0.83 (s, 9H), 0.82 (s, 9H), 0.10 (s, 3H), 0.08 (s, 3H), 0.05 (s,6H), 0.01 (s, 3H), 0.00 (s, 3H), −0.02 (s, 3H), −0.03 (s, 3H).

¹³C NMR (75 MHz, CDCl3) δ 208.4, 171.3, 159.4, 130.6, 129.3, 114.0,76.0, 72.9, 66.9, 64.1, 63.0, 61.4, 60.7, 60.6, 58.7, 58.5, 55.4, 34.1,26.4, 26.3, 26.2, 26.1, 26.0, 18.5, 18.4, 18.3, 18.2, 15.5, 14.4, 13.0,−4.3, −4.4, 4.6, −4.7, 4.9, −5.1, −5.2.

MS (ESI) m/z: 992 (M+23)⁺.

[α]²⁵ _(D) +39.7 (c 0.5, CH₂Cl₂).

R_(f)=0.45 (Hex:EtOAc, 4:1).

Example 42 Compound 17a

To a solution of 16a (289 mg, 0.3 mmol) in a mixture of CH₂Cl₂:H₂O(10:0.5 mL) was added 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (200 mg,0.89 mmol) at 23° C. The reaction mixture was stirred at 23° C. for 45min. Saturated aqueous solution of NaHCO₃ (30 mL) was added and themixture was extracted with CH₂Cl₂ (3×40 mL). The combined organic layerswere dried over Na₂SO₄, filtered, and concentrated under reducedpressure. The residue was solved in MeOH and NaBH₄ (35 mg, 0.95 mmol)was added and the reaction was stirred at 23° C. for 30 min. Then, thereaction was concentrated under reduced pressure. A saturated aqueoussolution of NaHCO₃ (20 mL) was added and the mixture was extracted withCH₂Cl₂ (3×30 mL). The combined organic layers were dried over Na₂SO₄,filtered, and concentrated under reduced pressure. The residue waspurified by flash column chromatography on silica gel (Hex:EtOAc, 6:1)to obtain 17a (153 mg, 60%) as a colourless oil.

¹H NMR (300 MHz, CDCl₃) δ 4.56-4.51 (m, 1H), 3.98-3.74 (m, 4H), 3.64 (s,3H), 3.61 (bs, 1H), 3.53 (d, J=3.9 Hz, 1H), 3.51-3.46 (m, 1H), 3.42-3.37(m, 1H), 3.23-3.18 (m, 1H), 3.14 (s, 3H), 2.69 (brd, J=6.3 Hz, 1H), 2.65(brd, J=5.1 Hz, 1H), 2.58 (d, J=9.6 Hz, 1H), 1.72-1.64 (m, 1H), 1.32 (s,3H), 0.95 (d, J=6.9 Hz, 3H), 0.90 (s, 9H), 0.88 (s, 9H), 0.87 (s, 9H),0.85 (s, 9H), 0.13 (s, 3H), 0.09 (s, 3H), 0.05 (s, 9H), 0.04 (s, 3H),0.03 (s, 3H), 0.00 (s, 3H).

¹³C NMR (75 MHz, CDCl₃) δ 212.7, 171.9, 75.6, 67.6, 65.5, 64.2, 63.2,61.4, 61.1, 60.9, 60.6, 60.4, 38.1, 35.7, 32.1, 31.9, 29.7, 26.0, 25.9,18.4, 18.3, 18.1, 18.0, 14.2, 14.2, −4.5, −4.6, −4.7, −5.2, −5.3, −5.4,−5.5.

MS (ESI) m/z: 872 (M+23)⁺.

[α]²⁵ _(D) −29.5 (c 0.5, CH₂Cl₂).

R_(f)=0.20 (Hex:EtOAc, 4:1).

Example 43 Compound 17b

To a solution of crude 16b (0.745 mmol) in a mixture of CH₂Cl₂:H₂O(10:0.5 mL) was added 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (507 mg,2.23 mmol) at 23° C. The reaction mixture was stirred at 23° C. for 40min. Saturated aqueous solution of NaHCO₃ (30 mL) was added and themixture was extracted with CH₂Cl₂ (3×40 mL). The combined organic layerswere dried over Na₂SO₄, filtered, and concentrated under reducedpressure. The residue was solved in MeOH and NaBH₄ (35 mg, 0.95 mmol)was added in portions during 2 h at 23° C. Then, the reaction wasconcentrated under reduced pressure. Saturated aqueous solution ofNaHCO₃ (20 mL) was added and the mixture was extracted with CH₂Cl₂ (3×30mL). The combined organic layers were dried over Na₂SO₄, filtered, andconcentrated under reduced pressure. The residue was purified by flashcolumn chromatography on silica gel (Hex:EtOAc, 6:1) to obtain 17b (474mg, 75% for 2 steps) as a colourless oil.

¹H NMR (300 MHz, CDCl₃) δ 4.58 (dt, J=9.9, 3.0 Hz, 1H), 4.13-3.99 (m,3H), 3.88 (td, J=9.0, 2.4 Hz, 2H), 3.64 (s, 3H), 3.60 (dd, J=8.7, 4.0Hz, 1H), 3.54-3.45 (m, 1H), 3.43 (d, J=═3.6 Hz, 1H), 3.24 (dt, J=9.9,3.0 Hz, 1H), 3.15-3.13 (m, 1H), 3.11 (s, 3H), 2.56-2.48 (m, 1H), 2.42(d, J=9.6 Hz, 1H), 2.30 (dd, J=16.2,2.4 Hz, 1H), 1.27 (s, 3H), 0.93 (s,9H), 0.91 (m, 3H), 0.88 (s, 9H), 0.86 (s, 18H), 0.15 (s, 3H), 0.14 (s,3H), 0.12 (s, 3H), 0.07 (s, 6H), 0.04 (s, 6H), 0.01 (s, 3H).

13C NMR (75 MHz, CDCl₃) δ 213.0, 171.4, 74.6, 65.7, 65.5, 64.1, 63.6,63.5, 62.3, 61.1, 60.1, 59.1, 35.9, 34.8, 32.0, 29.6, 26.1, 26.0, 25.8,25.7, 18.5, 18.3, 17.9, 14.2, 14.0, −4.5, −4.7, −5.0, −5.2, −5.3, −5.5,−5.6.

MS (ESI) m/z: 872 (M+23)⁺.

[α]²⁵ _(D) −14.4 (c 0.5, CH₂Cl₂).

R_(f)=0.30 (Hex:EtOAc, 4:1).

Example 44 Compound 17c

To a solution of 15b (289 mg, 0.3 mmol) in a mixture of CH₂Cl₂:H₂O(10:0.5 mL) was added 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (200 mg,0.89 mmol) at 23° C. The reaction mixture was stirred at 23° C. for 30min. Saturated aqueous solution of NaHCO₃ (30 mL) was added and themixture was extracted with CH₂Cl₂ (3×40 mL). The combined organic layerswere dried over Na₂SO₄, filtered, and concentrated under reducedpressure. The residue was solved in MeOH and NaBH₄ (35 mg, 0.95 mmol)was added and the reaction was stirred at 23° C. for 30 min. Then, thereaction was concentrated under reduced pressure. A saturated aqueoussolution of NaHCO₃ (20 mL) was added and the mixture was extracted withCH₂Cl₂ (3×30 mL). The combined organic layers were dried over Na₂SO₄,filtered, and concentrated under reduced pressure. The residue waspurified by flash column chromatography on silica gel (Hex:EtOAc, 7:1)to obtain 17c (61 mg, 24%) as a white solid.

¹H NMR (300 MHz, CDCl₃) δ 4.70-4.66 (m, 1H), 4.05-4.03 (m, 2H),3.85-3.81 (m, 3H), 3.68 (s, 3H), 3.67-3.65 (m, 1H), 3.50 (br t, J=9.3Hz, 2H), 3.38 (d, J=7.5 Hz, 1H), 3.18 (bs, 3H), 2.64 (d, J=8.7 Hz, 1H),2.50 (dd, J=15.0, 1.8 Hz, 1H), 2.09-2.07 (m, 1H), 2.00-1.95 (m, 1H),1.78-1.77 (m, 1H), 1.27 (s, 3H), 1.09 (d, J=6.9 Hz, 3H), 0.91 (s, 9H),0.88 (s, 9H), 0.87 (s, 9H), 0.85 (s, 9H), 0.84 (s, 9H), 0.14 (s, 3H),0.08 (s, 3H), 0.07 (s, 3H), 0.06 (s, 3H), 0.05 (s, 3H), 0.04 (s, 3H),0.03 (s, 3H), −0.02 (s, 3H).

MS (ESI) m/z: 874 (M+23)⁺.

R_(f)=0.26 (Hex:EtOAc, 4:1).

Example 45 Compound 18a

To a solution of 17a (113 mg, 0.13 mmol) in CH₂Cl₂ (2 mL) was addedDess-Martin periodinane (141 mg, 1.33 mmol) and catalytic amount ofNaHCO₃ at 23° C. The reaction mixture was stirred at 23° C. for 40 min.A saturated aqueous solution of NaHCO₃ (10 mL) was added and the mixturewas extracted with CH₂Cl₂ (3×10 mL). The combined organic layers weredried over Na₂SO₄, filtered, and concentrated under reduced pressure togive the corresponding aldehyde (Rf=0.33 Hex:EtOAc 4:1). Meanwhile, to asuspension of ethyl triphenylphosphonium bromide (395 mg) in toluene (7mL) was added 1M/THF potassium t-butoxide (0.85 mL) at 0° C. Theresulting orange solution was stirred at 0° C. for 25 min and thencooled to −78° C. Then, a solution of the fresh crude aldehyde intoluene (5 mL) was added dropwise to the previous suspension at −78° C.and the mixture was allowed to reach 23° C. during 14 h. The reactionmixture was diluted with CH₂Cl₂ (10 mL) and washed with a saturatedNaHCO₃ solution (15 mL). The organic phase was dried over MgSO₄,filtered, and concentrated in vacuo. The residue was purified by flashcolumn chromatography on silica gel (Hex:EtOAc, 15:1) to obtain 18a (80mg, 70% for 2 steps) as a colourless oil.

1H NMR (300 MHz, CDCl₃) δ 5.52-5.41 (m, 1H), 5.26 (td, J=10.2, 1.5 Hz,1H), 4.73-4.68 (m, 1H), 3.81 (dd, J=10.5, 4.5 Hz, 1H), 3.75-3.69 (m,2H), 3.63 (s, 3H), 3.60 (s, 2H), 3.29-3.24 (m, 1H), 3.22-3.16 (m, 1H),3.14 (s, 3H), 2.71 (d, J=9.3 Hz, 1H), 2.65 (brd, J=7.2 Hz, 1H), 2.52(dd, J=15.9, 3.3 Hz, 1H), 2.44-2.35 (m, 1H), 1.61 (dd, J=6.9, 1.5 Hz,3H), 1.29 (s, 3H), 1.10 (d, J=6.3 Hz, 3H), 0.89 (s, 9H), 0.88 (s, 9H),0.87 (s, 9H), 0.86 (s, 9H), 0.14 (s, 3H), 0.10 (s, 3H), 0.06 (s, 3H),0.05 (s, 6H), 0.04 (s, 3H), 0.01 (s, 3H), 0.00 (s, 3H).

¹³C NMR (75 MHz, CDCl₃) δ 211.2, 172.2, 130.9, 124.2, 76.7, 67.7, 64.9,62.8, 62.2, 61.1, 60.7, 59.5, 57.3, 37.7, 31.8, 29.7, 26.2, 26.0, 25.9,25.8, 18.9, 18.3, 18.2, 18.1, 18.1, 13.1, 12.3, −4.3, −4.4, −4.7, −4.9,−5.3, −5.4, −5.5.

MS (ESI) m/z: 882 (M+23)⁺.

R_(f)=0.52 (Hex:EtOAc, 4:1).

Example 46 Compound 18b

To a solution of 17b (474 mg, 0.557 mmol) in CH₂Cl₂ (10 mL) was addedDess-Martin periodinane (590 mg, 1.39 mmol) and catalytic amount ofNaHCO₃ at 23° C. The reaction mixture was stirred at 23° C. for 40 min.A saturated aqueous solution of NaHCO₃ (30 mL) was added and the mixturewas extracted with CH₂Cl₂ (3×40 mL). The combined organic layers weredried over Na₂SO₄, filtered, and concentrated under reduced pressure togive the corresponding aldehyde (R_(f)=0.38 Hex:EtOAc 4:1). Meanwhile,to a suspension of ethyl triphenylphosphonium bromide (1.64 g) intoluene (15 mL) was added 1M/THF potassium t-butoxide (3.56 mL) at 0° C.The resulting orange solution was stirred at 0° C. for 25 min and thencooled to −78° C. Then, a solution of the fresh crude aldehyde intoluene (10 mL) was added dropwise to the previous suspension at −78° C.and the mixture was allowed to reach 23° C. during 14 h. The reactionmixture was diluted with CH₂Cl₂ (20 mL) and washed with a saturatedNaHCO₃ solution (30 mL). The organic phase was dried over MgSO₄,filtered, and concentrated in vacuo. The residue was purified by flashcolumn chromatography on silica gel (Hex:EtOAc, from 15:1 to 10:1) toobtain 18b (347 mg, 72% for 2 steps) as a colourless oil.

¹H NMR (300 MHz, CDCl₃) δ 5.51-5.45 (m, 1H), 5.29 (td, J=11.1, 1.5 Hz,1H), 4.76-4.71 (m, 1H), 3.98 (dd, J=9.6, 3.3 Hz, 1H), 3.90 (dd, J=9.6,7.2 Hz, 1H), 3.69-3.68 (m, 2H), 3.65 (s, 3H), 3.59 (d, J=8.7 Hz, 1H),3.36-3.30 (m, 1H), 3.15 (s, 3H), 2.92-2.88 (m, 1H), 2.62 (d, J=9.3 Hz,1H), 2.58 (d, J=2.1 Hz, 1H), 2.55-2.52 (m, 1H), 2.43-2.35 (m, 1H), 1.61(dd, J=6.6, 1.5 Hz, 3H), 1.26 (s, 3H), 1.10 (d, J=6.6 Hz, 3H), 0.92 (s,9H), 0.86 (s, 9H), 0.85 (s, 9H), 0.84 (s, 9H), 0.12 (s, 3H), 0.09 (s,9H), 0.03 (s3H), 0.00 (s, 9H).

¹³C NMR (75 MHz, CDCl₃) δ 208.63, 172.3, 130.9, 124.2, 76.2, 66.7, 65.0,62.5, 61.3, 61.1, 60.0, 56.8, 36.7, 31.8, 29.7, 26.2, 25.9, 25.9, 18.9,18.3, 18.2, 18.1, 18.0, 13.1, 12.0, −4.5, −4.7, −4.8, −4.9, −5.2, −5.3,−5.5.

MS (ESI) m/z: 882 (+23)⁺.

[α]²⁵ _(D) +73.9 (c 0.5, CH₂Cl₂).

R_(f)=0.50 (Hex:EtOAc, 4:1).

Example 47 Compound 18c

Following the procedure described in example 45, 17c (60 mg, 0.07 mmol)was converted to 18c (30 mg, 50%, pale yellow oil) after purification ofthe crude product by flash column chromatography (Hex:EtOAc 10:1).

¹H NMR (300 MHz, CDCl₃) δ 5.48-5.40 (m, 1H), 5.32-5.25 (m, 1H),4.85-4.80 (m, 1H), 4.10 (dd, J=11.1, 2.4 Hz, 1H), 4.01 (brt, J=9.0 Hz,1H), 3.83 (dd, J=10.2, 5.4 Hz, 1H), 3.76 (br d, J=10.8 Hz, 1H), 3.66 (s,3H), 3.62 (d, J=10.2 Hz, 1H), 3.52 (dd, J=10.2. 6.0 Hz, 1H), 3.37 (d,J=8.4 Hz, 1H), 3.16 (s, 3H), 2.71 (d, J=9.3 Hz, 1H), 2.61-2.58 (m, 1H),2.50-2.39 (m, 2H), 2.03-2.00 (m, 1H), 1.77 (br d, J=8.4 Hz, 1H), 1.59(dd, J=6.6, 1.5 Hz, 3H), 1.24 (s, 3H), 1.13 (d, J=6.9 Hz, 3H), 0.91 (s,9H), 0.90 (s, 9H), 0.86 (s, 9H), 0.85 (s, 9H), 0.15 (s, 3H), 0.13 (s,3H), 0.10 (s, 6H), 0.08 (s, 3H), 0.03 (s, 3H), 0.01 (s, 3H).

MS (ESI) m/z: 862 (M+1)⁺.

R_(f)=0.48 (Hex:EtOAc, 4:1).

Example 48 Compound 19a

To a solution of 18a (80 mg, 0.093 mmol) in THF (1.5 mL) was addedBrMgEt (0.28 mL, 1.0 M in THF, 0.28 mmol) at 23° C. The reaction mixturewas stirred at 23° C. for 3 h. Saturated aqueous solution of NaHCO₃ (10mL) was added and the mixture was extracted with CH₂Cl₂ (3×15 mL). Thecombined organic layers were dried over Na₂SO₄, filtered, andconcentrated under reduced pressure. The residue was purified by flashcolumn chromatography on silica gel (Hex:EtOAc, 30:1) to obtain 19a (57mg, 75%) as a white solid.

¹H NMR (300 MHz, CDCl₃) d 5.53-5.43 (m, 1H), 5.26 (td, J=10.2, 1.5 Hz,1H), 4.71-4.66 (m, 1H), 3.77 (dd, J=10.8, 4.5 Hz, 1H), 3.67 (d, J=5.7Hz, 2H), 3.60 (t, J=9.3 Hz, 1H), 3.50 (d, J=8.7 Hz, 1H), 3.34-3.27 (m,1H), 3.20-3.14 (m, 1H), 2.64 (d, J=9 Hz, 1H), 2.58-2.56 (m, 2H),2.41-2.34 (m, 3H), 1.61 (dd, J=6.6, 1.8 Hz, 3H), 1.29 (s, 3H), 1.10 (d,J=6.3 Hz, 3H), 1.00 (t, J=7.5 Hz, 3H), 0.89 (s, 18H), 0.87 (s, 9H), 0.86(s, 9H), 0.15 (s, 3H), 0.10 (s, 3H), 0.05 (s, 3H), 0.04 (s, 6H), 0.03(s, 6H), 0.00 (s, 3H).

¹³C NMR (75 MHz, CDCl₃) δ 211.9, 209.2, 130.9, 124.4, 77.3, 67.4, 65.0,62.7, 62.1, 60.8, 59.8, 57.6, 47.2, 37.1, 31.7, 29.7, 26.3, 26.0, 25.9,25.8, 18.9, 18.4, 18.3, 18.1, 18.0, 13.1, 12.2, 7.5, −4.2, −4.3, −4.7,−5.0, −5.3, −5.5, −5.6.

MS (ESI) m/z: 851 (M+23)⁺.

[α]²⁵ _(D) −11.3 (c 0.5, CH₂Cl₂).

R_(f)=0.74 (Hex:EtOAc, 4:1).

Example 49 Compound 19b

To a solution of 18b (347 mg, 0.4 mmol) in THF (4 mL) was added 1M/THFBrMgEt (1.5 mL, 1.5 mmol) at 23° C. The reaction mixture was stirred at23° C. for 3 h. Saturated aqueous solution of NaHCO₃ (30 mL) was addedand the mixture was extracted with CH₂Cl₂ (3×30 mL). The combinedorganic layers were dried over Na₂SO₄, filtered, and concentrated underreduced pressure. The residue was purified by flash columnchromatography on silica gel (Hex:EtOAc, 40:1) to obtain 19b (280 mg,84%) as a colourless oil.

¹H NMR (300 MHz, CDCl₃) δ 5.54-5.44 (m, 1H), 5.30 (td, J=10.2, 1.5 Hz,1H), 4.71-4.67 (m, 1H), 3.95 (dd, J=9.6, 3.3 Hz, 1H), 3.91-3.85 (m, 1H),3.69 (d, J=1.5 Hz, 1H), 3.67 (s, 3H), 3.57 (d, J=9.0 Hz, 1H), 3.34-3.27(m, 1H), 2.89-2.84 (m, 1H), 2.62-2.58 (m, 1H), 2.60 (d, J=9.3 Hz, 1H),2.44-2.30 (m, 4H), 1.61 (dd, J=6.9, 1.5 Hz, 3H), 1.25 (s, 3H), 1.11 (d,J=6.6 Hz, 3H), 1.02 (t, J=7.5 Hz, 3H), 0.90 (s, 9H), 0.86 (s, 9H), 0.85(s, 9H), 0.82 (s, 9H), 0.13 (s, 3H), 0.10 (s, 3H), 0.09 (s, 6H), 0.01(s, 3H), 0.00 (s, 9H).

¹³C NMR (75 MHz, CDCl₃) δ 209.0, 208.7, 130.9, 124.1, 76.0, 65.8, 64.9,62.3, 61.3, 58.0, 57.2, 46.7, 36.7, 31.8, 26.2, 25.9, 25.8, 18.8, 18.3,18.2, 18.1, 18.0, 13.1, 12.1, 7.5, −4.5, −4.6, −4.8, −4.9, −5.3, −5.4,−5.5.

MS (ESI) m/z: 851 (M+23)⁺.

[α]²⁵ _(D) +69.5 (c 0.5, CH₂Cl₂).

R_(f)=0.76 (Hex:EtOAc, 4:1).

Example 50 Compounds 20a and 20c

To a solution of 19a (160 mg, 0.19 mmol) in THF (6 mL) was addedsimultaneously TBAF (1.52 mL, 1.0 M in THF, 1.52 mmol) and AcOH (77 μL,1.35 mmol) at 23° C. The reaction mixture was stirred at 23° C. for 16h. H₂O (10 mL) was added and the mixture was extracted with EtOAc (3×10mL). The combined organic layers were dried over Na₂SO₄, filtered, andconcentrated under reduced pressure. The residue was purified by flashcolumn chromatography on silica gel (Hex:EtOAc from 4:1 to 1:1) toobtain a tautomer equilibrium of 20a and 20c (77 mg, 82%) as a whitesolid.

¹H NMR (500 MHz, CDCl₃) (data of the major product) δ 5.54-5.49 (m, 1H),5.24 (m, 1H), 4.79 (d, J=2.5 Hz, 1H), 4.30 (dd, J=12.0 Hz, 1H), 3.84(dd, J=12.5, 4.0 Hz, 1H), 3.67-3.66 (m, 2H), 3.33 (d, J=10.0 Hz, 1H),3.30-3.26 (m, 1H), 2.77 (ddd, J=11.5, 5.0, 2.5 Hz, 1H), 2.51 (d, J=8.5Hz, 1H), 2.45-2.39 (m, 1H), 2.02 (dd, J=14.0, 3.5 Hz, 1H), 1.73 (dd,J=14.0, 3.0 Hz, 1H), 1.63 (dd, J=7.0, 1.5 Hz, 3H), 1.61-1.58 (m, 2H),1.31 (s, 3H), 1.12 (d, J=6.5 Hz, 3H), 0.93 (t, J=7.5 Hz, 3H), 0.86 (s,9H), 0.11 (s, 3H).

¹³C NMR (125 MHz, CDCl₃) (data of the major product) δ 213.1, 130.5,124.8, 97.3, 78.6, 65.3, 65.2, 62.2, 61.3, 55.5, 55.2, 54.7, 37.3, 34.5,31.6, 29.7, 26.0, 18.7, 13.3, 11.4, 7.4, −4.4, −5.2.

MS (ESI) m/z: 509 (M+23)⁺, 451 (M+H−2×H₂O)⁺.

R_(f)=0.56 (Hex:EtOAc, 1:2).

Example 51 Compounds 20b and 20d

Following the procedure described in example 50, 19b (35 mg, 0.04 mmol)was converted to a tautomer equilibrium of 20b and 20d (12 mg, 60%, paleyellow oil) after purification of the crude product by flash columnchromatography (Hex:EtOAc from 4:1 to 1:1).

¹H NMR (500 MHz, CDCl₃) (data of the major product) δ 5.56-5.50 (m, 1H),5.32-5.26 (m, 1H), 4.38 (ddd, J=15.5, 11.5, 5.0 Hz, 1H), 3.86-3.76 (m,4H), 3.53 (d, J=9.5 Hz, 1H), 3.24-3.20 (m, 1H), 2.89 (ddd, J=14.5, 11.0,4.5 Hz, 1H), 2.59 (d, J=9.5 Hz, 1H), 2.46-2.41 (m, 1H), 2.08 (dd,J=12.5, 5.0 Hz, 1H), 1.69-1.66 (m, 2H), 1.64 (dd, J=7.0, 2.0 Hz, 3H),1.46 (dd, J=13.0, 12.0 Hz, 1H), 1.30 (s, 3H), 1.13 (d, J=7.0 Hz, 3H),0.97 (t, J=7.5 Hz, 3H), 0.86 (s, 3H), 0.14 (s, 3H), 0.00 (s, 3H).

¹³C NMR (125 MHz, CDCl₃) (data of the major product) δ 213.1, 130.6,124.7, 98.8, 77.0, 66.8, 65.1, 62.2, 60.8, 60.0, 59.0, 40.1, 35.5, 31.5,29.7, 26.1, 18.8, 18.2, 13.3, 11.5,7.4, −4.3, −5.0.

MS (ESI) m/z: 509 (M+23)⁺, 451 (M+H−2×H₂O)⁺.

[α]²⁵ _(D) +55.0 (c 0.5, CH₂Cl₂).

R_(f)=0.51 (Hex:EtOAc, 1:2).

Example 52 Compounds 3a and 4a

To a solution of 19a (238 mg, 0.29 mmol) in DMF (5 mL) was addedsimultaneously TBAF (2.9 mL, 1.0 M in THF, 2.9 mmol) and AcOH (116 μL, 2mmol) at 23° C. The reaction mixture was stirred at 23° C. for 7 h.Saturated aqueous solution of NaHCO₃ (10 mL) was added and the mixturewas extracted with EtOAc (3×10 mL). The combined organic layers weredried over Na₂SO₄, filtered, and concentrated under reduced pressure.The residue was purified by flash column chromatography on silica gel(Hex:EtOAc from 4:1 to 0: 1) to obtain a tautomer equilibrium of 3a and4a (25 mg, 23%) as a colourless oil.

¹H NMR (500 MHz, CD₃OD) (data of the major product) δ 5.56-5.51 (m, 1H),5.31-5.26 (m, 1H), 4.75 (m, 1H), 4.29 (dd, J=11.5, 11.5 Hz, 1H), 3.72(dd, J=12.5, 4.0 Hz, 1H), 3.67-3.62 (m, 2H), 3.29-3.27 (m, 1H), 3.16 (d,J=10.0 Hz, 1H), 2.89 (ddd, J=11.5, 4.5, 2.0 Hz, 1H), 2.59. (d, J=9.5 Hz,1H), 1.93 (dd, J=14.0, 3.0 Hz, 1H), 1.75 (dd, J=14.5, 3.0 Hz, 1H), 1.65(dd, J=6.5, 2.0 Hz, 3H), 1.56 (q, J=7.5 Hz, 2H), 1.34 (s, 3H), 1.09 (d,J=7.0 Hz, 3H), 0.92 (t, J=7.5 Hz, 3H).

¹H NMR (500 MHz, CDCl₃) (data of the major product) δ 5.55-5.48 (m, 1H),5.27-5.20 (m, 1H), 4.74 (brd, J=2.0 Hz, 1H), 4.32 (dd, J=13.0, 13.0 Hz,1H), 3.89 (dd, J=12.5, 4.0 Hz, 1H), 3.76 (dd, J=10.0, 9.0 Hz, 1H), 3.63(dd, J=10.5, 3.5 Hz, 1H), 3.33 (d, J=9.5 Hz, 1H), 3.29 (dd, J=9.5, 4.0Hz, 1H), 2.94 (ddd, J=11.5, 5.0, 2.5 Hz, 1H), 2.68 (d, J=9.0 Hz, 1H),2.44-2.39 (m, 1H), 2.02 (dd, J=14.0, 3.0 Hz, 1H), 1.73 (dd, J=14.0, 3.0Hz, 1H), 1.62 (dd, J=7.0, 1.5 Hz, 3H), 1.59-1.56 (m, 2H), 1.33 (s, 3H),1.11 (d, J=6.0 Hz, 3H), 0.94 (t, J=7.5 Hz, 3H).

¹³C NMR (125 MHz, CDCl₃) (data of the major product) δ 214.2, 130.0,125.0, 97.3, 77.2, 66.8, 66.7, 65.2, 63.0, 55.6, 54.6, 52.9, 37.1, 34.5,31.3, 18.6, 13.3, 11.6, 7.4.

MS (ESI) m/z: 767 (2×M+23)⁺, 395 (M+23)+, 377 (M+23−H₂O)⁺.

R_(f)=0.24 (Hex:EtOAc, 1:2).

Example 53 Compounds 3b and 4b

Following the procedure described in example 52, 19b (200 mg, 0.24 mmol)was converted to a tautomer equilibrium of 3b and 4b (20 mg, 21%) afterpurification of the crude product by flash column chromatography(Hex:EtOAc from 4:1 to 0: 1).

¹H NMR (500 MHz, CDCl₃) (data of the major product) d 5.56-5.48 (m, 1H),5.28-5.22 (m, 1H), 4.41-4.37 (m, 1H), 3-97-3.73 (m, 5H), 3.34-3.22 (m,1H), 2.98 (ddd, J=4.5 Hz, 11.5 Hz, 14.5 Hz, 1H), 2.73 (d, J=9 Hz, 1H),2.46-2.42 (m, 1H), 2.09 dd, J=5 Hz, 13 Hz, 1H), 1.67 (q, J=7 Hz, 2H),1.63 (dd, J=1.5 Hz, 7 Hz, 3H), 1.48-1.48-1.42 (m, 1H), 1.35 (s, 3H),1.11 (d J=7 Hz, 3H), 0.96 (t, J=7 Hz, 3H).

MS (ESI) m/z: 395 (M+23)⁺, 767 (2M+23)⁺, 377 (M+23−H₂O)⁺, 337(M+1−2H₂O)⁺, 319 (M+1−3H₂O)⁺. HRMS (TOF) Calcd for C₁₉H₃₂O₇Na: 395.2046.Found 395.2019.

R_(f)=0.15 (Hex:EtOAc, 1:2).

Example 54 Compound 21

Compound 21 was prepared following the procedure described by D. A.Evans et al., J. Am. Chem. Soc. 1984, 106,4261-4263.

¹H NMR (300 MHz, CDCl₃) δ 7.21 (m, 1H), 7.12 (m, 1H), 4.44 (m, 1H), 4.20(m, 2H), 2.36 (m, 1H), 1.91 (dd, J=6.6, 1.2 Hz, 3H), 0.88 (d, J=6.9 Hz,3H), 0.83 (d, J=6.9 Hz, 3H).

Example 55 Compound 22

To a solution of 21 (9.39g, 0.047 mol) in CH₂Cl₂ (75 mL) was addedBu₂BOTf (52.4 mL, 1.0 M in CH₂Cl₂, 52.4 mmol) and Et₃N (9.3 mL, 0.067mol) at −78° C. The reaction mixture was stirred 1 h at −78° C., 15 minat 0° C. and recooled at −78° C. This solution was added over a solutionof 8a (9 g, 0.016 mol) in CH₂Cl₂ (25 mL) at −50° C. and the mixture wasstirred at −50° C. for an additional 10 days. Then, saturated aqueoussolution of NH₄Cl (150 mL) was added and the reaction was extracted withCH₂Cl₂ (2×100 mL). The combined organic layers were dried over Na₂SO₄,filtered, and concentrated under reduced pressure. The residue waspurified by flash column chromatography on silica gel (Hex:EtOAc, from15:1 to 2:1) to afford compound 22 alone with ca. 15% of anotherdiastereoisomer (12 g, 80%) as a colourless oil.

¹H NMR (300 MHz, CDCl₃) δ 7.20 (d, J=8.7 Hz, 2H), 6.86 (d, J=8.7 Hz,2H), 6.20 (dt, J=17.4, 10.2 Hz, 1H), 5.25 (dd, J=11.1, 0.6 Hz, 1H), 5.20(dd, J=19.2, 0.6 Hz, 1H), 4.47-4.33 (m, 3H), 4.28-4.09 (m, 3H), 3.95 (br d, J=3.6 Hz, 1H), 3.80 (s, 3H), 3.65-3.56 (m, 2H), 3.33 (br d, J=7.2Hz, 2H), 2.90 (d, J=9.3 Hz, 1H), 2.45-2.35 (m, 1H), 2.33-2.23 (q, J=6.9Hz, 1H), 1.83-1.73 (m, 1H), 1.56-1.46 (m, 1H), 1.28 (s, 3H), 1.03 (d,J=6.9 Hz, 3H), 0.90 (s, 9H), 0.87 (s, J=6.9Hz, 3H), 0.83 (s, J=6.9 Hz,3H), 0.82 (s, 9H), 0.09 (s, 3H), 0.08 (s, 3H), 0.06 (s, 3H), 0.05 (s,3H).

¹³C NMR (75 MHz, CDCl₃) δ 172.9, 158.7, 153.0, 132.1, 128.7, 128.3,118.8, 113.3, 77.0, 74.6, 72.3, 69.0, 64.7, 64.5, 63.0, 62.9, 62.7,60.0, 58.5, 58.1, 58.0, 54.7, 50.4, 47.1, 32.9, 32.2, 30.9, 28.1, 27.9,27.3, 25.6, 25.5, 17.8, 17.6, 14.3, 14.3, 14.2, 14.1, −5.1, −5.3, −5.8,−5.9.

MS (ESI) m/z: 786 (M+23)⁺, 764 (M+H)⁺.

R_(f)=0.32 (Hex:EtOAc, 4:1).

Example 56 Compound 23

To a solution of the mixture of diastereoisomers (5:1) of 22 (3.9 g, 5.1mmol) in THF:H₂O (5:1, 75 mL), LiBH₄ (13 mL, 2.0 M in THF, 26 mmol) wasadded at 0° C. The reaction mixture was stirred 30 min at 0° C. and 2.5h at 23° C. Saturated aqueous solution of NH₄Cl (100 mL) was added andthe mixture was extracted with EtOAc (3×150 mL). The combined organiclayers were dried over Na₂SO₄, filtered, and concentrated under reducedpressure. The residue 23 (3.4 g) was used in the next step with nofurther purification.

¹H NMR (300 MHz, CDCl₃) δ 7.17 (d, J=8.4 Hz, 2H), 6.85 (d, J=9.0 Hz,2H), 6.17-6.05 (m, 1H), 5.20 (dd, J=═10.5, 1.8 Hz, 1H), 5.13 (dd,J=17.7, 1.8 Hz, 1H), 4.40-4.35 (m, 2H), 4.02 (d, J=9.6 Hz, 1H),3.85-3.73 (m, 2H), 3.80 (s, 3H), 3.48-3.47 (m, 2H), 3.39-3.34 (m, 1H),3.30-3.24 (m, 1H), 2.66 (d, J=9.3 Hz, 1H), 2.31-2.28 (m, 1H), 1.81-1.74(m, 2H), 1.28 (s, 3H), 1.05 (d, J=6.6 Hz, 3H), 0.92 (s, 9H), 0.86 (s,9H), 0.17 (s, 3H), 0.12 (s, 3H), 0.00 (s, 3H), −0,01 (s, 3H).

¹³C NMR (75 MHz, CDCl₃) δ 159.4, 135.8, 130.3, 129.2, 118.3, 114.0,79.1, 73.2, 73.0, 72.3, 67.2, 65.6, 64.4, 60.4, 55.4, 47.7, 46.7, 33.6,26.2, 18.5, 18.2, 15.0, 12.9, −4.1, −5.0, −5.1, −5.4.

MS (ESI) m/z: 661 (M+23)⁺, 639 (M+H)⁺.

R_(f)=0.18 (Hex:EtOAc, 4:1).

Example 57 Compound 24

To a solution of crude 23 (5 mmol) in CH₂Cl₂ (60 mL) was added imidazole(1.02 g, 15 mmol) and TBSCl (1.13 g, 7.5 mmol) at 23° C. The reactionmixture was stirred at 23° C for 15 min. A saturated aqueous solution ofNH₄Cl (70 mL) was added and the reaction was extracted with CH₂Cl₂(2×100 mL). The combined organic layers were dried over Na₂SO₄,filtered, and concentrated under reduced pressure. The residue waspurified by flash column chromatography on silica gel (Hex:EtOAc, 20:1)to obtain pure compound 24 (1.7 g, 43% for two steps) as a colourlessoil.

¹H NMR (300 MHz, CDCl3) δ 7.19 (d, J=8.7 Hz, 2H), 6.86 (d, J=8.7 Hz,2H), 5.96-5.84 (m, 1H), 5.12-5.05 (m, 2H), 4.37 (q, J=11.4 Hz, 2H), 4.0(d, J=9.3 Hz, 1H), 3.92 (s, 1H), 3.86-3.77 (m, 2H), 3.80 (s, 3H),3.57-3.46 (m, 3H), 3.37-3.29 (m, 2H), 2.67 (d, J=9.3 Hz, 1H), 2.42-2.36(m, 1H), 1.83-1.76 (m, 2H), 1.30 (s, 3H), 1.06 (d, J=6.9 Hz, 3H), 0.93(s, 9H), 0.88 (s, 9H), 0.87 (s, 9H), 0.17 (s, 3H), 0.12 (s, 3H), 0.03(s, 9H), 0.00 (s, 3H).

¹³C NMR (75 MHz, CDCl₃) δ 159.4, 136.0, 130.4, 129.2, 118.0, 114.0,79.2,73.1, 72.9, 68.2, 65.3, 64.7, 64.6, 60.7, 55.4, 49.1, 47.1, 33.6,26.3, 26.2, 26.1, 18.5, 15.1, 12.9, −4.1, −4.9, −5.1, −5.2, −5.3.

MS (ESI) m/z: 775 (M+23)⁺, 753 (M+H)⁺.

[α]²⁵ _(D) −8.0 (c 0.50, CH₂Cl₂).

R_(f)=0.65 (Hex:EtOAc, 4:1).

Example 58 Compound 25a

Over a solution of 24 (1.58 g, 2.09 mmol) in CH₂Cl₂ (40 mL) was bubbleda current of O₃ during 2 min at −78° C. Then, Ph₃P (1.65 g, 6.27 mmol)was added and the mixture was allowed to warm to room temperature, andthe stirring was continued for 1.5 h. The mixture was concentrated underreduced pressure and the residue was purified by flash columnchromatography on silica gel (Hex:EtOAc, 20:1) to afford compound 25a(1.34 g, 85%) as a colourless oil.

¹H NMR (300 MHz, CDCl₃) δ 9.77 (d, J=3.0 Hz, 1H), 7.21 (d, J=8.7 Hz,2H), 6.89 (d, J=8.7 Hz, 2H), 4.39 (s, 2H), 4.18 (dd, J=9.9, 7.8 Hz, 1H),4.08 (m, 1H), 4.04-4.03 (m, 1H), 3.90 (dd, J=9.9, 6.0 Hz, 1H), 3.81 (s,3H), 3.73-3.68 (m, 2H), 3.55-3.50 (dd, J=10.5, 3.3 Hz, 1H), 3.40-3.27(m, 2H), 2.67 (d, J=9.3 Hz, 1H), 2.62 (m, 1H), 1.98-1.92 (m, 1H),1.83-1.74 (m, 1H), 1.27 (s, 3H), 1.05 (d, J=6.9 Hz, 3H), 0.92 (s, 9H),0.86 (s, 9H), 0.85 (s, 9H), 0.17 (s, 3H), 0.11 (s, 3H),0.05 (s, 6H),0.02 (s, 3H), 0.00 (s, 3H).

¹³C NMR (75 MHz, CDCl₃) δ 205.6, 159.4, 130.3, 129.4 114.1, 79.2, 73.2,72.9, 70.4, 65.5, 64.0, 61.7, 60.9, 55.8, 55.4, 47.4, 33.6, 26.2, 26.0,18.4, 18.2, 15.0, 12.9, −4.1, −5.0, 5.2, −5.3, −5.3, −5.4.

MS (ESI) m/z: 777 (M+23)⁺.

[α]²⁵ _(D) −7.9 (c 0.52, CH₂Cl₂).

R_(f)=0.67 (Hex:EtOAc, 4:1).

Example 59 Compound 25b

To a solution of 25a (1.34 mg, 1.78 mmol) in CH₂Cl₂ (50 mL) was addedDess-Martin periodinane (1.5 mg, 3.56 mmol) and catalytic amount ofNaHCO₃ at 23° C. The reaction mixture was stirred at 23° C. for 50 min.A saturated aqueous solution of NaHCO₃ (60 mL) was added and the mixturewas extracted with CH₂Cl₂ (3×70 mL). The combined organic layers weredried over Na₂SO₄, filtered, and concentrated under reduced pressure togive aldehyde 25b which was used in the next step with no furtherpurification.

¹H-NMR (300 MHz, CDCl₃): δ 9.59 (d, J=2.7 Hz, 1H), 7.23 (d, J=8.6 Hz,2H), 6.88 (d, J=8.6 Hz, 2H), 4.36-4.48 (m, 2H), 4.22-4.29 (m, 1H),3.98-4.07 (m, 1H), 3.81-3.88 (m, 1H), 3.80 (s, 3H), 3.64-3.78 (m, 2H),3.32-3.45 (m, 4H), 2.47 (d, J=9.3 Hz, 1H), 1.68-1.81 (m, 1H), 1.24 (s,3H), 1.03 (d, J=6.7 Hz, 3H), 0.92 (s, 9H), 0.91 (s, 9H), 0.90 (s, 9H),0.06 (s, 3H), 0.05 (s, 3H), 0.03 (s, 3H), 0.02 (s, 3H), -0.01 (s, 3H),−0.02 (s, 3H).

R_(f)=0.69 (Hex:EtOAc, 4:1).

Example 60 Compounds 26a and 26b

To a solution of N-methoxy-N-methylacetamide (70 μL g, 0.65 mmol) in THF(2 mL) at −78° C. was added bis-(trimethylsilyl)-lithiumamid (0.65 mL,1.0 M in THF, 0.65 mmol) and the reaction mixture was stirred for 1 h atthat temperature. Then, a solution of 25a (165 mg, 0.22 mmol) in THF (4mL) was added over the previous solution and the reaction mixture wasstirred for an additional 1 h at −78° C. Then, a saturated aqueoussolution of NH₄Cl (30 mL) was added and the reaction was extracted withEtOAc (3×50 mL). The combined organic layers were dried over Na₂SO₄,filtered, and concentrated under reduced pressure. The residue waspurified by flash column chromatography on silica gel (Hex:EtOAc from4:1 to 1:1) to yield 26a and 26b (1:2) as colourless oils (139 mg, in acombined 74% of yield).

¹H NMR (300 MHz, CDCl₃) mix of diastereoisomers δ 7.19-7.25 (m, 2H),6.82-6.89 (m, 2H), 4.58-4.63 (m, 1H), 4.36-4.55 (m, 2H), 4.01-4.08 (m,1H), 5.75-5.98 (m, 3H), 3.80 (s, 1.98H), 3.79 (s, 1.02H), 3.65 (s,1.98H), 3.64 (s, 1-02H), 3.44-3.65 (m, 2H), 3.25-3.32 (m, 2H), 3.17 (s,1.02H), 3.16 (s, 1.98H), 2.80-2.88 (m, 1H), 2.69 (d, J=9.3 Hz, 0.66H),2.68 (d, J ═9.0 Hz, 0.34H), 2.65-2.74 (m, 1H), 2.00-2.09 (m, 1H),1.74-1.88 (m, 2H), 1.69 (br s, 1H), 1-34 (s, 1.02H), 1.25 (s, 1.98H),1.07 (m, 3H), 0.92 (s, 5.94H), 0.90 (s, 3.06H), 0.89 (s, 3.06H), 0.88(s, 5.94H), 0.85 (s, 3.06H), 0.83 (s, 5.94H), −0.02-0.18 (m, 18H).

MS (ESI) m/z: 880 (M+23)⁺, 858 (M+1)⁺.

R_(f)=0.09 (Hex:EtOAc, 4:1).

Example 61 Compounds 26c and 26d

To a solution of N-methoxy-N-methylacetamide (568 μL g, 5.34 mmol) inTHF (15 mL) at −78° C. was added bis-(trimethylsilyl)-lithiumamid (1.0 Min THF) (5.34 mL, 5.34 mmol) and the reaction mixture was stirred for 1h at that temperature. Then, a solution of crude 25b (1.78 mmol) in THF(25 mL) was added over the previous solution and the reaction mixturewas stirred for an additional 3 h at −78° C. Then, a saturated aqueoussolution of NH₄Cl (50 mL) was added and the reaction was extracted withEtOAc (3×60 mL). The combined organic layers were dried over Na₂SO₄,filtered, and concentrated under reduced pressure. The residue waspurified by flash column chromatography on silica gel (Hex:EtOAc from4:1 to 2:1) to yield 26c and 26d (1:1.9) as colourless oils (910 mg, ina combined 60% of yield for two steps).

¹H NMR (300 MHz, CDCl₃) mix of diastereoisomers δ 7.25 (d, J=8.7 Hz,4H), 6.88 (d, J=8.4 Hz, 4H), 4.64-4.60 (m, 1H), 4.48-4.36 (m, 6H),4.10-3.82 (m, 6H), 3.80 (s, 6H), 3.76-3.71 (m, 2H), 3.66 (s, 6H), 3.61(d, J=3.3 Hz, 1H), 3.53-3.48 (m, 2H), 2.44-3.29 (m, 6H), 3.18 (s, 6H),3.01-2.80 (m, 3H), 2.61 (m, 1H), 2.57 (d, J=9.0 Hz, 1H), 2.53 (d, J=9.0Hz, 1H), 1.81-1.67 (m, 2H), 1.32 (s, 3H), 1.31 (s, 3H), 1.05 (d, J=6.9Hz, 6H), 0.89 (s, 18 H), 0.87 (s, 9H), 0.86 (s, 9H), 0.85 (s, 9H), 0.84(s, 9H), 0.1 (s, 6H), 0.07 (s, 9H), 0.06 (s, 3H), 0.02 (s, 3H), 0.01 (s,6H), 0.00 (s, 3H), −0.01 (s, 3H), −0.01 (s, 3H),

¹³C NMR (75 MHz, CDCl₃) δ 211.0, 172.4, 159.0, 130.1, 128.9, 113.6,77.0, 72.6, 72.0, 71.9, 67.4, 66.1, 64.1, 64.0, 63.1, 63.0, 61.0, 60.8,60.5, 60.1, 59.8, 58.9, 56.7, 55.1, 36.3, 33.5, 26.0, 25.7, 18.2, 18.0,15.0, 12.5, −4.6, −4.7, −5.0, −5.1, −5.5, −5.6.

MS (ESI) m/z: 878 (M+23)⁺.

R_(f)=0.44 (Hex:EtOAc, 2:1). Also R_(f)=0.16 (Hex:EtOAc, 4:1).

Example 62 Compounds 27a and 27b

To a solution of a mixture of 26a and 26b (139 mg, 0.16 mmol) in CH₂Cl₂(8 mL) was added 2,6-lutidine (57 μL, 0.49 mmol) and TBSOTf (56 μL, 0.24mmol) at 0° C. The reaction mixture was stirred at 0° C. for 30 min.Then, a saturated aqueous solution of NH₄Cl (30 mL) was added, and thereaction was extracted with CH₂Cl₂ (2×25 mL). The combined organiclayers were dried over Na₂SO₄, filtered, and concentrated under reducedpressure. The residue was purified by flash column chromatography onsilica gel (Hex:EtOAc 10:1) to obtain 27a (white solid) and 27b(colourless oil) (1:2) (113 mg in a combined 72% of yield).

27a: ¹H NMR (300 MHz, CDCl₃) δ 7.28 (d, J=8.7 Hz, 2H), 6.87 (d, J=8.7Hz, 2H), 4.66 (brd, J=9.9 Hz, 1H), 4.50 (dd, J=11.7 Hz, 2H), 4.10 (brd,J=9.6 Hz, 1H), 3.92 (d, J=6.6 Hz, 2H), 3.80 (s, 3H), 3.66 (s, 3H),3.64-3.59 (m, 2H), 3.42-3.85 (m, 1H), 3.35-3.32 (m, 1H), 3.15 (s, 3H),3.01-2.96 (m, 1H), 2.74 (d, J=9.3 Hz, 1H), 2.70-2.67 (m, 1H), 2.08-2.03(m, 1H), 1.92 (bs, 1H), 1.79-1.70 (m, 1H), 1.37 (s, 3H), 1.07 (d, J=6.6Hz, 3H), 0.91 (s, 9H), 0.90 (s, 9H), 0.88 (s, 9H), 0.85 (s, 9H), 0.16(s, 3H), 0.12 (s, 3H), 0.08 (s, 3H), 0.03 (s, 6H), 0.02 (s, 6H), 0.00(s, 3H).

MS (ESI) m/z: 994 (M+23)⁺.

R_(f)=0.34 (Hex:EtOAc, 4:1).

27b: ¹H NMR (300 MHz, CDCl₃) δ 7.24 (d, J=8.7 Hz, 2H), 6.86 (d, J=8.7Hz, 2H), 4.82-4.80 (m, 1H), 4.43 (q, J=11.4 Hz, 2H), 3.96-3.92 (m, 1H),3.80 (s, 3H), 3.76-3.75 (m, 1H), 3.66 (s, 3H), 3.69-3.58 (m, 3H), 3.46(dd, J=9.0, 6.3 Hz, 1H), 3.31 (dd, J=9.0, 7.2 Hz, 1H), 3.15 (s, 3H),3.00-2.93 (m, 1H), 2.69 (d, J=8.7 Hz, 1H), 2.69-2.62 (m, 1H), 2.02-1.94(m, 2H), 1.80-1.73 (m, 1H), 1.65 (s, 1H), 1.33 (s, 3H), 1.09 (d, J=6.6Hz, 3H), 0.91 (s, 9H), 0.89 (s, 9H), 0.87 (s, 9H), 0.85 (s, 9H), 0.17(s, 3H), 0.12 (s, 3H), 0.10 (s, 3H), 0.07 (s, 3H), 0.05 (s, 3H), 0.03(s, 3H), 0.02 (s, 3H), 0.02 (s, 3H).

MS (ESI) m/z: 994 (M+23)⁺.

R_(f)=0.46 (Hex:EtOAc, 4:1).

Example 63 Compound 27c

To a solution of 27a (36 mg, 0.04 mmol) in CH₂Cl₂ (4 mL) was addedDess-Martin periodinane (63 mg, 0.15 mmol) and catalytic amount ofNaHCO₃ at 23° C. The reaction mixture was stirred at 23° C. for 1.5 h.Saturated aqueous solution of NaHCO₃ (10 mL) was added and the mixturewas extracted with CH₂Cl₂ (3×10 mL). The combined organic layers weredried over Na₂SO₄, filtered, and concentrated under reduced pressure.The residue was purified by flash column chromatography on silica gel(Hex:EtOAc, 10:1) to obtain 27c (26 mg, 72%) as a pale yellow oil. Thiscompound is also obtained by protection of 26c with TBSOTf and lutidinewith a quantitative yield under standard condition.

¹H NMR (300 MHz, CDCl₃) δ 7.22 (d, J=8.7 Hz, 2H), 6.86 (d, J=8.7 Hz,2H), 4.80-4.78 (m, 1H), 4.41 (q, J=11.4 Hz, 2H), 4.15 (d, J=4.5 Hz, 2H),3.80 (s, 3H), 3.75-3.67 (m, 2H), 3.64 (s, 3H), 3.61-3.50 (m, 3H), 3.39(dd, J=9.3, 7.2 Hz, 1H), 3.29 (dd, J=9.3, 6.6 Hz, 1H), 3.15 (bs, 3H),2.99-2.96 (m, 1H), 2.67 (d, J=9.3 Hz, 1H), 2.54 (br d, J=5.1 Hz, 1H),1.33 (s, 3H), 1.06 (d, J=6.3 Hz, 3H), 0.90 (s, 9H), 0.85 (s, 18H), 0.84(s, 9H), 0.09 (s, 3H), 0.08 (s, 3H), 0.06 (s, 3H), 0.02 (s, 3H), 0.01(s, 6H), −0.01 (s, 3H).

¹³C NMR (75 MHz, CDCl₃) δ 210.2, 172.5, 159.1, 130.2, 128.9, 113.7,76.1, 72.6, 72.1, 67.0, 64.0, 63.8, 61.5, 61.0, 60.8, 58.1, 55.1, 54.2,36.7, 33.6, 29.6, 26.0, 25.9, 25.8, 25.7, 18.2, 18.1, 18.0, 17.9, 15.1,13.4, −4.8, −4.9, −4.9, −5.4, −5.5, −5.5, −5.6.

MS (ESI) m/z: 992 (M+23)⁺, 970 (M+1)⁺.

[α]²⁵ _(D) =45.1 (c 0.50, CH₃Cl).

R_(f)=0.38 (Hex:EtOAc, 4:1).

Example 64 Compound 27d

To a solution of 27b (77 mg, 0.08 mmol) in CH₂Cl₂ (3 mL) was addedDess-Martin periodinane (63 mg, 0.15 mmol) and catalytic amount ofNaHCO₃ at 23° C. The reaction mixture was stirred at 23° C. for 1.5 h.Saturated aqueous solution of NaHCO₃ (10 mL) was added and the mixturewas extracted with CH₂Cl₂ (3×10 mL). The combined organic layers weredried over Na₂SO₄, filtered, and concentrated under reduced pressure.The residue was purified by flash column chromatography on silica gel(Hex:EtOAc, 10:1) to obtain 27d (51 mg, 66%) as a pale yellow oil. Thiscompound is also obtained by protection of 26d with TBSOTf and lutidinewith a quantitative yield under standard condition.

¹H NMR (300 MHz, CDCl₃) δ 7.23 (d, J=8.7 Hz, 2H), 6.87 (d, J=8.7 Hz,2H), 4.47 (d, J=12.0 Hz, 1H), 4.36 (d, J=12.0 Hz, 1H), 3.99-3.83 (m,3H), 3.80 (s, 3H), 3.69-3.58 (m, 2H), 3.68 (s, 3H), 3.42-3.36 (m, 2H),3.26 (dd, J=9.3, 6.3 Hz, 1H), 3.17 (bs, 3H), 3.07 (dt, J=9.3, 3.3 Hz,1H), 2.90-2.87 (m, 1H), 2.59 (d, J=9.0 Hz, 1H), 2.17 (br d, J=14.1 Hz,1H), 1.31 (s, 3H), 1.05 (d, J=6.6 Hz, 3H), 0.90 (s, 9H), 0.88 (s, 9H),0.85 (s, 9H), 0.84 (s, 9H), 0.18 (s, 3H), 0.12 (s, 3H), 0.08 (s, 3H),0.07 (s, 3H), 0.06 (s, 3H), −0.01 (s, 6H), -0.02 (s, 3H).

¹³C NMR (75 MHz, CDCl₃) δ 209.2, 172.1, 159.2, 130.2, 129.0, 113.8,76.3, 72.5, 71.8, 68.2, 64.2, 63.0, 61.3, 60.9, 60.0, 59.3, 57.7, 55.1,36.4, 34.0, 29.6, 26.4, 25.9, 25.8, 25.7, 18.7, 18.1, 17.9, 15.3, 12.4,−4.3, −4.4, −5.1, −5.2, −5.5, −5.6, −5.7.

MS (ESI) m/z: 992 (M+23)⁺.

[α]²⁵ _(D) +47.6 (c 0.5, CH₃Cl).

R_(f)=0.45 (Hex:EtOAc, 4:1).

Example 65 Compound 28a

To a solution of 27c (390 mg, 0.4 mmol) in a mixture of CH₂Cl₂:H₂O(4:0.2 mL) was added 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (274 mg,1.2 mmol) at 23° C. The reaction mixture was stirred at 23° C. for 18min. Saturated aqueous solution of NaHCO₃ (15 mL) was added and themixture was extracted with CH₂Cl₂ (3×15 mL). The combined organic layerswere dried over Na₂SO₄, filtered, and concentrated under reducedpressure. The residue was solved in MeOH and NaBH₄ (74 mg, 2 mmol) wasadded and the reaction was stirred at 23° C. for 30 min. Then, thereaction was concentrated under reduced pressure. A saturated aqueoussolution of NaHCO₃ (20 mL) was added and the mixture was extracted withCH₂Cl₂ (3×30 mL). The combined organic layers were dried over Na₂SO₄,filtered, and concentrated under reduced pressure. The residue waspurified by flash column chromatography on silica gel (Hex:EtOAc, 4:1)to obtain 28a (220 mg, 65%) as a white solid.

¹H NMR (300 MHz, CDCl₃) δ 4.77-4.72 (m, 1H), 4.10-3.99 (m, 2H),3.86-3.84 (m, 2H), 3.65 (s, 3H), 3.62-3.59 (m, 1H), 3.56-3.48 (m, 3H),3.15 (s, 3H), 2.99-2.95 (m, 1H), 2.76-2.75 (m, 1H), 2.58-2.55 (m, 1H),2.52 (br d, J=3.3 Hz, 1H), 2.46 (d, J=9.3 Hz, 1H), 1.67 (bs, 1H), 1.37(s, 3H), 1.01 (d, J=6.9 Hz, 3H), 0.90 (s, 9H), 0.89 (s, 9H), 0.86 (s,9H), 0.85 (s, 9H), 0.12 (s, 3H), 0.11 (s, 3H), 0.08 (s, 3H), 0.07 (s,3H), 0.06 (s, 3H), 0.03 (s, 3H), 0.02 (s, 3H), 0.01 (s, 3H).

¹³C NMR (75 MHz, CDCl₃) δ 211.8, 172.1, 76.9, 67.1, 65.1, 64.8, 63.4,61.5, 61.2, 61.1, 58.5, 57.3, 36.6, 35.8, 32.0, 29.6, 26.0, 25.9, 25.8,25.7, 18.2, 18.1, 17.9, 14.3, 13.7, −4.6, −4.8, −5.2, −5.4, −5.5, −5.6.

MS (ESI) m/z: 872 (M+23)⁺.

[α]²⁵ _(D) −32.9 (c 0.50, CH₃Cl).

R_(f)=0.31 (Hex:EtOAc, 4:1).

Example 66 Compound 28b

To a solution of 27d (718 mg, 0.74 mmol) in a mixture of CH₂Cl₂:H₂O(10:0.5 mL) was added 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (504 mg,2.22 mmol) at 23° C. The reaction mixture was stirred at 23° C. for 17min. Saturated aqueous solution of NaHCO₃ (15 mL) was added and themixture was extracted with CH₂Cl₂ (3×15 mL). The combined organic layerswere dried over Na₂SO₄, filtered, and concentrated under reducedpressure. The residue was solved in MeOH and NaBH₄ (110 mg, 3 mmol) wasadded and the reaction was stirred at 23° C. for 20 min. Then, thereaction was concentrated under reduced pressure. A saturated aqueoussolution of NaHCO₃ (20 mL) was added and the mixture was extracted withCH₂Cl₂ (3×30 mL). The combined organic layers were dried over Na₂SO₄,filtered, and concentrated under reduced pressure. The residue waspurified by flash column chromatography on silica gel (Hex:EtOAc, 4:1)to obtain 28b (374 mg, 60%) as a white solid.

¹H NMR (300 MHz, CDCl₃) δ 4.75-4.72 (m, 1H), 4.02-3.92 (m, 2H), 3.88(dd, J=10.5, 3.9 Hz, 1H), 3.71-3.65 (m, 1H), 3.67 (s, 3H), 3.61-3.54 (m,2H), 3.49 (d, J=6.3 Hz, 1H), 3.45-3.39 (m, 1H), 3.16 (bs, 3H), 3.13-3.08(m, 1H), 2.84 (br dd, J=15.9, 8.7 Hz, 1H), 2.48 (d, J=9.0 Hz, 1H),2.46-2.44 (m, 1H), 1.72-1.67 (m, 1H), 1.31 (s, 3H), 1.09 (d, J=6.6 Hz,3H), 0.90 (s, 9H), 0.89 (s, 9H), 0.86 (s, 9H), 0.85 (s, 9H), 0.16 (s,3H), 0.12 (s, 3H), 0.09 (s, 3H), 0.08 (s, 3H), 0.07 (s, 3H), 0.06 (s,3H), 0.02 (s, 3H), 0.01 (s, 3H).

¹³C NMR (75 MHz, CDCl₃) δ 212.6, 172.0, 76.4, 67.6, 65.2, 65.0, 62.9,61.2, 61.1, 60.8, 59.9, 59.5, 37.1, 36.2, 32.0, 29.6, 26.0, 25.9, 25.8,25.6, 18.3, 18.1, 18.0, 18.0, 14.4, 13.5, −3.6, −4.4, −4.8, −4.9, −5.0,−5.5, −5.6, −5.7.

MS (ESI) m/z: 872 (M+23)⁺.

[α]²⁵ _(D) +21.6 (c 0.52, CH₃Cl).

R_(f)=0.31 (Hex:EtOAc, 4:1).

Example 67 Compound 29a

To a solution of 28a (162 mg, 0.19 mmol) in CH₂Cl₂ (5 mL) was addedDess-Martin periodinane (202 mg, 0.47 mmol) and catalytic amount ofNaHCO₃ at 23° C. The reaction mixture was stirred at 23° C. for 40 min.A saturated aqueous solution of NaHCO₃ (15 mL) was added and the mixturewas extracted with CH₂Cl₂ (3×20 mL). The combined organic layers weredried over Na₂SO₄, filtered, and concentrated under reduced pressure togive the corresponding aldehyde (R_(f)=0.32, Hex:EtOAc, 4:1). Meanwhile,to a suspension of ethyl triphenylphosphonium bromide (565 mg, 1.94mmol) in toluene (7 mL) was added potassium t-butoxide (1.24 mL, 1.0 Min THF, 1.24 mmol) at 0° C. The resulting orange solution was stirred at0° C. for 25 min and then cooled to −78° C. Then, a solution of thefresh crude aldehyde in toluene (5 mL) was added dropwise to theprevious suspension at −78° C. and the mixture was allowed to reach 23°C. during 14 h. The reaction mixture was diluted with CH₂Cl₂ (20 mL) andwashed with a saturated NaHCO₃ solution (30 mL). The organic phase wasdried over MgSO₄, filtered, and concentrated in vacuo. The residue waspurified by flash column chromatography on silica gel (Hex:EtOAc, from20:1) to obtain 29a (105 mg, 64% for 2 steps) as a white solid.

¹H NMR (300 MHz, CDCl₃) δ 5.52-5.46 (m, 1H), 5.26-5.19 (m, 1H),4.88-4.87 (m, 1H), 4.20-4.09 (m, 2H), 3.70-3.65 (m, 1H), 3.64 (s, 3H),3.60-3.57 (m, 3H), 3.42 (d, J=8.4 Hz, 1H), 3.15 (bs, 3H), 2.79-2.75 (m,1H), 2.58 (d, J=9.6 Hz, 1H), 2.43-2.39 (m, 2H), 1.62 (dd, J=6.6, 1.5 Hz,3H), 1.29 (s, 3H), 1.10 (d, J=6.6 Hz, 3H), 0.91 (s, 9H), 0.86 (s, 9H),0.85 (s, 9H), 0.84 (s, 9H), 0.10 (s, 3H), 0.09 (s, 6H), 0.08 (s, 3H),0.01 (s, 3H), 0.00 (s, 3H), −0.01 (s, 3H), −0.02 (s, 3H).

¹³C NMR (75 MHz, CDCl₃) δ 211.0, 171.9, 130.5, 124.0, 66.6, 64.8, 62.6,61.9, 61.6, 60.6, 57.0, 53.7, 36.2, 31.1, 29.2, 25.7, 25.5, 25.4, 25.3,18.4, 17.8, 17.7, 17.6, 12.7, 11.8, −5.1, −5.2, −5.3, −5.4, −5.8, −5.9,−6.0.

MS (ESI) m/z: 882 (M+23)⁺.

[α]²⁵ _(D) −26.1 (c 0.50, CH₂Cl₂).

R_(f)=0.44 (Hex:EtOAc, 4: 1).

Example 68 Compound 29b

To a solution of 28b (318 mg, 0.37 mmol) in CH₂Cl₂ (8 mL) was addedDess-Martin periodinane (397 mg, 0.93 mmol) and catalytic amount ofNaHCO₃ at 23° C. The reaction mixture was stirred at 23° C. for 40 min.A saturated aqueous solution of NaHCO₃ (30 mL) was added and the mixturewas extracted with CH₂Cl₂ (3×40 mL). The combined organic layers weredried over Na₂SO₄, filtered, and concentrated under reduced pressure togive the corresponding aldehyde (R_(f)=0.42, Hex:EtOAc, 4:1). Meanwhile,to a suspension of ethyl triphenylphosphonium bromide (1.1 g, 3.77 mmol)in toluene (12 mL) was added potassium t-butoxide (2.43 mL, 1M in THF,2.34 mmol) at 0° C. The resulting orange solution was stirred at 0° C.for 25 min and then cooled to −78° C. Then, a solution of the freshcrude aldehyde in toluene (6 mL) was added dropwise to the previoussuspension at −78° C. and the mixture was allowed to reach 23° C. during15 h. The reaction mixture was diluted with CH₂Cl₂ (20 mL) and washedwith a saturated NaHCO₃ solution (30 mL). The organic phase was driedover MgSO₄, filtered, and concentrated in vacuo. The residue waspurified by flash column chromatography on silica gel (Hex:EtOAc 20:1)to obtain 29b (195 mg, 60% for 2 steps) as a white solid.

¹H NMR (300 MHz, CDCl₃) δ 5.50-5.42 (m, 1H), 5.29-5.25 (m, 1H),4.81-4.78 (m, 1H), 3.93 (dd, J=11.4, 3.6 Hz, 1H), 3.81 (m, 2H), 3.67 (s,3H), 3.64-3.56 (m, 2H), 3.43-3.39 (m, 1H), 3.17 (bs, 3H), 3.03-3.00 (m,1H), 2.96-2.88 (m, 1H), 2.65 (d, J=9.0 Hz, 1H), 2.46-2.35 (m, 1H), 2.10(br d, J=14.7 Hz, 1H), 1.61 (dd, J=6.9, 1.8 Hz, 1H), 1.28 (s, 3H), 1.11(d, J=6.9 Hz, 3H), 0.90 (s, 9H), 0.87 (s, 9H), 0.85 (s, 9H), 0.84 (s,9H), 0.18 (s, 3H), 0.14 (s, 3H), 0.08 (s, 3H), 0.06 (s, 3H), 0.06 (s,3H), 0.01 (s, 3H), −0.02 (s, 3H), −0.03 (s, 3H).

¹³C NMR (75 MHz, CDCl₃) δ 209.0, 172.0, 131.0, 124.2, 76.3, 68.1, 65.0,62.6, 61.4, 61.3, 59.6, 59.4, 57.2, 36.3, 31.8, 29.7, 26.4, 25.9, 25.8,25.7, 18.9, 18.7, 18.1, 18.0, 17.9, 13.2, 11.9, −4.3, −4.4, −5.1, −5.2,−5.4, −5.5, −5.6.

MS (ESI) m/z: 882 (M+23)⁺.

[α]²⁵ _(D) +70.2 (c 0.50, CH₂Cl₂).

R_(f)=0.77 (Hex:EtOAc, 4:1).

Example 69 Compound 30a

To a solution of 29a (80 mg, 0.093 mmol) in THF (1.5 mL) was addedBrMgEt (0.28 mL, 1M in THF, 0.28 mmol) at 23° C. The reaction mixturewas stirred at 23° C. for 3 h. Saturated aqueous solution of NaHCO₃ (10mL) was added and the mixture was extracted with CH₂Cl₂ (3×15 mL). Thecombined organic layers were dried over Na₂SO₄, filtered, andconcentrated under reduced pressure. The residue was purified by flashcolumn chromatography on silica gel (Hex:EtOAc, 20:1) to obtain 30a (54mg, 71%) as a white solid.

¹H NMR (300 MHz, CDCl₃) δ 5.54-5.44 (m, 1H), 5.26-5.18 (m, 1H), 4.83(ddd, J=9.6, 4.2, 21. Hz, 1H), 4.13 (dd, J=9.6, 7.2 Hz, 1H), 4.05 (dd,J=9.6, 3.9 Hz, 1H), 3.67 (dd, J=8.7, 6.6 Hz, 1H), 3.59-3.57 (m, 2H),3.38 (d, J=9.0 Hz, 1H), 2.75-70 (m, 1H), 2.55 (d, J=9.3 Hz, 1H),2.46-2.43 (m, 5H), 1.62 (dd, J=6.6, 1.8 Hz, 3H), 1.28 (s, 3H), 1.10 (d,J=6.3 Hz, 3H), 1.01 (t, J=7.2 Hz, 3H), 0.91 (s, 9H), 0.86 (s, 9H), 0.85(s, 9H), 0.82 (s, 9H), 0.10 (s, 3H), 0.09 (s, 6H), 0.08 (s, 3H), 0.01(s, 3H), 0.00 (s, 3H), −0.01 (s, 3H), −0.03 (s, 3H).

¹³C NMR (75 MHz, CDCl₃) δ 212.5, 209.2, 131.1, 124.7, 78.2, 66.6, 65.5,63.2, 62.6, 62.4, 57.5, 54.3, 53.6, 47.3, 36.7, 31.8, 29.9, 26.3, 26.1,26.0, 19.0, 18.5, 18.3, 18.2, 13.4, 12.4, 7.8, −4.3, −4.4, −4.7, −4.8,−5.1, −5.2, −5.3.

MS (ESI) m/z: 851 (M+23)⁺.

[α]²⁵ _(D) −25.4 (c 0.50, CH₂Cl₂).

R_(f)=0.86 (Hex:EtOAc, 4:1).

Example 70 Compound 30b

To a solution of 29b (110 mg, 0.13 mmol) in THF (1.5 mL) was addedBrMgEt (0.38 mL, 1M in THF, 0.38 mmol) at 23° C. The reaction mixturewas stirred at 23° C. for 4 h. Saturated aqueous solution of NaHCO₃ (10mL) was added and the mixture was extracted with CH₂Cl₂ (3×15 mL). Thecombined organic layers were dried over Na₂SO₄, filtered, andconcentrated under reduced pressure. The residue was purified by flashcolumn chromatography on silica gel (Hex:EtOAc, 20:1) to obtain 30b (70mg, 65%) as a colourless oil.

¹H NMR (300 MHz, CDCl₃) δ 5.52-5.41 (m, 1H), 5.28-5.20 (m, 1H),4.76-4.72 (m, 1H), 3.85-3.73 (m, 3H), 3.70 (d, J=10.2 Hz, 1H), 3.48-3.41(m, 2H), 3.05-3.00 (dt, J=10.2, 3.3 Hz, 1H), 2.80 (dd, J=15.6, 10.5 Hz,1H), 2.64 (d, J=9.3 Hz, 1H), 2.45-2.40 (m, 3H), 2.38-2.12 (m, 1H), 1.61(dd, J=6.9, 1.8 Hz, 3H), 1.29 (s, 3H), 1.11 (d, J=6.3 Hz, 3H), 1.01 (t,J=7.2 Hz, 3H), 0.89 (s, 18H), 0.84 (s, 18H), 0.19 (s, 3H), 0.14 (s, 3H),0.05 (s, 3H), 0.03 (s, 6H), 0.01 (s, 3H), 0.00 (s, 3H), −0.04 (s, 3H).

¹³C NMR (75 MHz, CDCl₃) δ 209.5, 209.3, 131.0, 124.3, 76.0, 67.6, 64.9,62.4, 61.3, 59.8, 58.9, 57.3, 45.5, 38.1, 31.9, 29.7, 26.3, 25.9, 25.8,25.7, 19.0, 18.7, 18.1, 18.0, 17.8, 13.3, 11.9, 7.4, −4.1, −4.2, −5.1,−5.2, −5.4, −5.5, −5.6, −5.7.

MS (ESI) m/z: 851 (M+23)⁺.

[α]²⁵ _(D) +80.9 (c 0.50, CH₂Cl₂).

R_(f)=0.71 (Hex:EtOAc, 4:1).

Example 71 Compounds 31a and 31c

Following the procedure described in example 50, 30a (48 mg, 0.058 mmol)was converted to a tautomer equilibrium of 31a and 31c (20 mg, 70%,colourless oil) after purification of the crude product by flash columnchromatography (Hex:EtOAc from 4:1 to 1:1).

¹H NMR (500 MHz, CDCl₃) (data of the major product) d 5.55-5.49 (m, 1H),5.29-5.24 (m, 1H), 4.28 (ddd, J=15.5, 11.0, 4.5 Hz, 1H), 3.97 (dd,J=11.5, 11.5 Hz, 2H), 3.76 (dd, J=11.5, 3.5 Hz, 1H), 3.67-3.65 (m, 1H),3.62 (d, J=10.0 Hz, 1H), 3.35-3.31 (m, 1H), 2.86-2.80 (m, 1H), 2.60 (d,J=9.0 Hz, 1H), 2.44-2.37 (m, 1H), 2.09 (dd, J=12.5, 4.5 Hz, 1H),1.70-1.65 (m, 2H), 1.62 (dd, J=7.0, 2.0 Hz, 3H), 1.45 (br t, J=11.5 Hz,1H), 1.30 (s, 3H), 1.11 (d, J=7.0 Hz, 3H), 0.96 (t, J=7.5 Hz, 3H), 0.89(s, 9H), 0.16 (s, 3H), 0.05 (s, 3H).

¹³C NMR (125 MHz, CDCl₃) (data of the major product) δ 214.7, 130.5,124.8, 98.7, 78.2, 66.9, 65.0, 61.8, 60.5, 59.6, 59.2, 57.7, 39.9, 35.6,31.4, 26.1, 18.7, 18.4, 13.3, 11.6, 7.4, −4.4, −4.7.

MS (ESI) m/z: 509 (M+23)⁺, 451 (M+1−2×H₂O)⁺.

R_(f)=0.4 (Hex:EtOAc, 1:2).

Example 72 Compounds 31b and 31d

Following the procedure described in example 50, 30b (45 mg, 0.054 mmol)was converted to a tautomer equilibrium of 31b and 31d (13 mg, 50%,colourless oil) after purification of the crude product by flash columnchromatography (Hex:EtOAc from 4:1 to 1:1).

¹H NMR (500 MHz, CDCl₃) (data of the major product) δ 5.59-5.46 (m, 1H),5.28 (m, 1H), 4.62 (bs, 1H), 4.22 (dd, J=11.5, 11.5 Hz, 1H), 4.10 (dd,J=12.0, 5.0 Hz), 3.70-3.60 (m, 2H), 3.48 (d, J=10.0 Hz, 1H), 3.243.17(m, 1H), 2.94 (ddd, J=11.5, 5.0, 2.0 Hz, 1H), 2.61 (d, J=9.5 Hz, 1H),2.47-2.41 (m, 1H), 2.03 (dd, J=14.5, 3.5 Hz, ), 1.66 (dd, J=7.0, 1.5 Hz,3H), 1.63-1.61 (m, 2H), 1.58 (dd, J=14.0, 3.0 Hz, 1H), 1.32 (s, 3H),1.14 (d, J=6.0 Hz, 3H), 0.97 (t, J=7.5 Hz, 3H), 0.87 (s, 9H), 0.15 (s,3H), 0.00 (s, 3H).

¹³C NMR (125 MHz, CDCl₃) (data of the major product) δ 216.3, 130.5,124.9, 97.2, 78.4, 65.9, 65.2, 62.0, 60.7, 55.7, 55.4, 54.7, 37.1, 34.2,31.4, 26.0, 18.7, 18.2, 13.3, 11.4,7.4, −4.3, −5.2.

MS (ESI) m/z: 509 (M+23)⁺, 451 (M+1−2×H₂O)⁺.

R_(f)=0.42 (Hex:EtOAc, 1:2).

Example 73 Compounds 3c and 4c

Following the procedure described in example 52, 31a (48 mg, 0.058 mmol)was converted to a tautomer equilibrium of 3c and 4c (5 mg, 22%) afterpurification of the crude product by flash column chromatography(Hex:EtOAc from 4:1 to 0: 1).

¹H NMR (500 MHz, CDCl₃) (data of the major product) δ 5.56-5.49 (m, 1H),5.28-5.23 (m, 1H), 4.36 (ddd, J=15.0, 11.0, 5.0 Hz, 1H), 3.97-3.66 (m,4H), 3.62 (d, J=10.0 Hz, 1H), 3.25-3.18 (m, 1H), 2.98 (ddd, J=14.0,10.0, 4.0 Hz, 1H), 2.78 (d, J=9.0 Hz, 1H), 2.45-2.40 (m, 1H), 2.09 (dd,J=13.0, 5.0 Hz, 1H), 1.67 (q, J=7.5 Hz, 2H), 1.63 (dd, J=1.5 Hz, 7 Hz,3H), 1.48-1.42 (m, 1H), 1.33 (s, 3H), 1.12 (d J=7.0 Hz, 3H), 0.96 (t,J=7.5 Hz, 3H).

¹³C NMR (125 MHz, CDCl₃) (data of the major product) δ 215.4, 130.0,125.0, 98.7, 77.3, 67.0, 62.8, 60.8, 60.0, 59.0, 40.1, 35.5, 31.3, 23.9,19.7, 18.6, 13.3, 11.3, 7.4.

MS (ESI) m/z: 767 (2×M+23)⁺, 395 (M+23)⁺, 337 (M+1−2×H₂O)⁺.

R_(f)=0.16 (Hex:EtOAc, 1:2).

Example 74 Compounds 3d and 4d

Following the procedure described in example 52, 31b (150 mg, 0.18 mmol)was converted to a tautomer equilibrium of 3d and 4d (10 mg, 15%) afterpurification of the crude product by flash column chromatography(Hex:EtOAc from 4:1 to 0:1).

¹H NMR (500 MHz, CH₃OD) (data of the major product) δ 5.57-5.51 (m, 1H),5.32-5.26 (m, 1H), 4.80 (m, 1H), 4.26 (dd, J=11.5, 11.5 Hz, 1H),3.98-3.60 (m, 3H), 3.31-3.29 (m, 1H), 3.24 (d, J=10 Hz,1H), 2.80 (ddd,J=11.5, 4.5, 2.5 Hz, 1H), 2.59 (d, J=9.5 Hz, 1H), 1.95 (dd, J=14.0, 3.5Hz, 1H), 1.75 (dd, J=14.5, 3.0 Hz, 1H), 1.65 (dd, J=6.5, 15. Hz, 3H),1.56 (q, J=7.5 Hz, 2H), 1.34 (s, 3H), 1.10 (d, J=7.0 Hz, 3H), 0.92 (t,J=7.5Hz,3H).

¹H NMR (500 MHz, CDCl₃) (data of the major product) δ 5.56-5.50 (m, 1H),5.36 (s, 1H), 5.27-5.21 (m, 1H), 4.76 (bs, 1H), 4.29 (dd, J=11.5, 11.5Hz, 1H), 3.87 (dd, J=12.5, 4.0Hz, 1H), 3.73-3.62 (m, 3H), 3.46 (d,J=10.0 Hz,1H), 2.90 (ddd, J=11.5, 4.5, 2.0 Hz, 1H), 2.74 (d, J=9.5 Hz,1H),2.01 (dd, J=13.5, 3.5 Hz, 1H), 1.70 (dd, J=14.0, 2.5 Hz, 1H), 1.62(dd, J=7.0, 2.0 Hz, 3H), 1.61-1.59 (m, 2H), 1.34 (s, 3H), 1.11 (d, J=6.5Hz, 3H), 0.95 (t, J=7.0 Hz, 3H).

¹³C NMR (125 MzH, CDCl₃) (data of the major product) δ 214.9, 130.0,125.1, 96.9, 77.1, 67.1, 65.4, 62.8, 60.9, 55.3, 54.9, 52.7, 37.4, 34.2,31.3, 18.6, 13.3, 11.4, 7.5.

MS (ESI) m/z: 767.2 (2×M+23)⁺, 395.3 (M+23)⁺, 377.3 (M+23−H₂O)⁺, 337(M+1−2×H₂O)⁺, 319.3 (M+1−3×H₂O)⁺.

R_(f)=0.22 (Hex:EtOAc, 1:2).

Example 75 Compound 32

This compound was obtained as a side product in the preparation of 34from 11a. To a solution of 11a (1.72 g, 2.69 mmol) in acetone (10 mL)was added dimethoxypropane (10 mL) and camphorsulfonic acid (94 mg, 0.4mmol) and the mixture was stirred for 1 h at 23° C. (until TLC revealedtotal consumption of the starting material). Et₃N (0.56 mL, 4 mmol) wasthen added and the mixture was stirred for 30 min. Solvents were removedunder reduced pressure and the mixture was subjected to flash columnchromatography on silica gel (Hex:EtOAc, from 10:1 to 3:1) affordingfurano 32 (0.6 g, 35%) as a colourless oil.

¹H NMR (300 MHz, CDCl₃) δ 7.23 (d, J=8.8 Hz, 2H), 6.87 (d, J=8.8 Hz,2H), 5.72-5.65 (m, 1H), 5.09-5.06 (m, 2H), 4.42 (s, 2H), 4.44-4.39 (m,1H), 3.90 (dd, J=10.0, 2.0 Hz, 1H), 3.84-3.78 (m, 2H), 3.80 (s, 3H),3.60 (dd, J=6.0, 5.5 Hz, 1H), 3.51-3.42 (m, 3H), 3.36-3.32 (m, 2H),2.76-2.73 (m, 1H), 2.63-2.58 (m, 1H), 2.13-2.09 (m, 1H), 1.98 (d, J=4.5Hz, 1H), 1.02 (d, J=6.8 Hz, 3H), 0.99 (s, 3H), 0.92 (s, 9H), 0.90 (s,9H), 0.11 (s, 3H), 0.10 (s, 3H), 0.09 (s, 3H), 0.07 (s, 3H).

¹³C NMR (75 MHz, CDCl₃) δ 159.1, 137.4, 130.5, 129.1, 116.3, 113.7,83.6, 78.7, 77.7, 77.1, 75.4, 72.7, 64.9, 58.6, 55.2, 49.6, 34.4, 25.8,25.7, 18.1, 18.0, 17.5, 12.5, −4.7, −5.1, −5.5−.5.6.

MS (ESI) m/z: 661.4 (M+23)⁺.

R_(f)=0.35 (Hex:EtOAc, 4:1).

Example 76 Compounds 33 and 42

To a solution of furane 32 (246 mg, 0.346 mmol) in CH₂Cl₂ (10 mL) andwater (0.5 mL) was added 2,3-dichloro-5,6-dicyanol,4-benzoquinone (236mg, 1.04 mmol) and the reaction mixture was vigorously stirred for 1 hat 23° C. The reaction was hydrolysed by addition of aqueous NaHCO₃ (20mL) and the solution was extracted with CH₂Cl₂ (2×20 mL). The combinedorganic layers were dried over Na₂SO₄, filtered and concentrated invacuo. The residue was dissolved in MeOH (5 mL) and treated with NaBH₄(30 mg) for 30 min at 23° C. After this time, solvents were removedunder reduced pressure, and the residue was dissolved in CH₂Cl₂,hydrolysed with aqueous NH₄Cl and extracted with CH₂Cl₂ (2×20 mL). Thecombined organic layers were dried over Na₂SO₄, filtered andconcentrated in vacuo. The residue was purified by flash columchromatography on silica gel (Hex:EtOAc, from 4:1 to 2:1) to obtaincompounds 33 (88 mg, 40%) and 42 (77 mg, 42%) as colourless oils.

33: ¹H NMR (300 MHz, CDCl₃) δ 5.82-5.75 (m, 1H), 5.46 (s, 1H), 5.13-5.09(s, 2H), 4.48 (d, J=6.5 Hz, 1H), 4.07-4.04 (m, 1H), 3.99 (dd, J=4.5, 4.0Hz, 1H), 3.97-3.94 (m, 1H), 3.91 (d, J=2.5 Hz, 1H), 3.88-3.79 (m, 2H),3.81 (s, 3H), 3.62 (dd, J=6.0, 5.0 Hz, 1H), 3.50-3.43 (m, 1H), 3.28-3.22(m, 1H), 2.76-2.67 (m, 2H), 1.76-1.71 (m, 1H), 1.26 (d, J=7.0 Hz, 3H),1.08 (s, 3H), 0.91 (s, 9H), 0.87 (s, 9H), 0.10 (s, 3H), 0.08 (s, 3H),0.04 (s, 3H), −0.07 (s, 3H).

¹³C NMR (75 MHz, CDCl₃) δ 159.8, 137.4, 131.3, 127.4, 116.3, 113.5,102.1, 86.4, 83.4, 79.4, 77.0, 75.4, 65.1, 58.7, 55.2, 49.9, 46.2, 30.6,29.7, 25.8, 18.6, 18.1, 13.3, −4.3, −5.2, −5.4, −5.5.

MS (ESI) m/z: 659.2 (M+23)⁺.

R_(f)=0.31 (Hex:EtOAc, 4:1).

42: ¹H NMR (300 MHz, CDCl₃) δ 5.68-5.55 (m, 1H), 5.18-5.12 (m, 2H), 4.41(d, J=6.7 Hz, 1H), 3.94-3.77 (m, 3H), 3.70-3.36 (m, 3H), 3.14 (d, J=8.6Hz, 1H), 2.82-2.77 (m, 1H), 2.64-2.59 (m, 1H), 2.04-2.03 (m, 1H),1.89-1.82 (m, 1H), 1.04 (s, 3H), 0.97 (d, J=6.7 Hz, 3H), 0.92 (s, 9H),0.90 (s, 9H), 0.13 (s, 3H), 0.11 (s, 6H), 0.09 (s, 3H).

¹³C NMR (75 MHz, CDCl₃) δ 136.3, 118.4, 82.9, 80.3, 79.7, 79.1, 66.4,64.7, 58.4, 49.5, 47.0, 39.1, 26.1, 26.0, 18.4, 18.3, 16.5, 15.2, −4.4,−5.0, −5.2, −5.3.

MS (ESI) m/z: 541.2 (M+23)⁺, 519.3 (M+1)⁺.

R_(f)=0.06 (Hex:EtOAc, 4:1).

Example 77 Compound 34

To a solution of 11a (1.72 g, 2.69 mmol) in acetone (10 mL) was addeddimethoxypropane (10 mL) and camphorsulfonic acid (94 mg, 0.4 mmol) andthe mixture was stirred for 1 h at 23° C. (until TLC revealed totalconsumption of the starting material). Et₃N (0.56 mL, 4 mmol) was thenadded and the mixture was stirred for 30 min. Solvents were removedunder reduced pressure and the mixture was subjected to flash columnchromatography on silica gel (Hex:EtOAc, from 10:1 to 3:1) affordingacetonide 34 (1.16 g mg, 64%) as a colourless oil.

¹H NMR (300 MHz, CDCl₃) δ 7.20 (d, J=8.4 Hz, 2H), 6.87 (d, J=8.4 Hz,2H), 6.30-6.17 (m, 1H), 5.13 (dd, J=10.2, 2.1 Hz, 1H), 5.09 (dd, J=16.8,2.1 Hz, 1H), 4.37 (ss, J=15.6, 1.7 Hz, 2H), 4.19 (dd, J=7.2, 2.1 Hz,1H), 4.10 (dd, J=11.4, 2.7 Hz, 1H), 3.80 (s, 3H), 3.68 (d, J=6.0 Hz,1H),3.64-3.57 (m, 2H), 3.49 (dd, J=10.2, 6.0 Hz, 1H), 3.39-3.28 (m, 2H),2.55 (d, J=9.3 Hz, 1H), 2.27 (d, J=9.6 Hz, 1H), 2.04-1.72 (m, 2H), 1.43(s, 3H), 1.36 (s, 3H), 1.27 (3, 3H), 1.06 (d, J=6.9 Hz, 3H), 0.92 (s,9H), 0.86 (s, 9H), 0.12 (s, 3H), 0.07 s, 3H), 0.00 (s, 3H), −0,01 (s,3H).

¹³C NMR (75 MHz, CDCl₃) δ 159.1, 137.2, 130.1, 129.1, 117.1, 113.7,98.8, 76.5, 72.9, 72.7, 67.8, 66.2, 64.8, 64.5, 58.4, 55.2, 44.9, 44.0,33.5, 29.8, 26.1, 25.9, 18.8, 18.3, 18.0, 14.9, 13.2, −4.5, −4.6, −5.3,−5.5.

MS (ESI) m/z: 701 (M+23)⁺.

R_(f)=0.67 (Hex:EtOAc, 4:1).

Example 78 Compound 35a

To a solution of 14a (32 mg, 0.037 mmol) in acetone (1.5 mL) was addeddimethoxypropane (1.5 mL) and camphorsulfonic acid (0.85 mg, 0.0037mmol) and the mixture was stirred for 1 h at 23° C. (until TLC revealedtotal consumption of the starting material). Et₃N (14 μL, 0.01 mmol) wasthen added and the reaction was stirred for 30 min. Solvents wereremoved under reduced pressure and the mixture was subjected to flashcolumn chromatography on silica gel (Hex:EtOAc, 4:1) affording acetonide35a (27 mg, 81%) as a colourless oil.

¹H NMR (300 MHz, CDCl₃) δ 7.25 (d, J=8.8 Hz, 2H), 6,87 (d, J=8.8 Hz,2H), 4.49-4.38 (m, 3H), 3.82-3.74 (m, 2H), 3.80 (s, 3H), 3.70-3.30 (m3H), 3.18 (s, 3H), 2.96 (d, J=9.1 Hz, 1H), 2.74-2.60 (m, 1H), 2.52 (d,J=8.6 Hz, 1H), 2.56-2.46 (m, 1H), 2.42-2.36 (m, 1H), 2.04-1.90 (m, 1H),1.82-1.58 (m 2H), 1.32 (s, 3H), 1.30 (s, 3H), 1.25 (s, 3H), 1.12 (d,J=6.5 Hz, 3H), 0.92 (s, 9H), 0.89 (s, 9H), 0.87 (s, 9H), 0.17 (s, 3H),0.10 (s, 3H), 0.08 (s, 3H), 0.05 (s, 3H), 0.03 (s, 3H), 0.02 (s, 3H).

¹³C NMR (75 MHz, CDCl₃) δ 173.1, 159.4, 130.7, 129.4, 114.0, 100.9,78.2, 73.0, 72.2, 67.2, 65.6, 64.0, 63.4, 61.4, 60.8, 59.8, 55.5, 50.5,46.5, 39.0, 33.4, 30.0, 26.5, 26.3, 25.2, 25.5, 18.7, 18.4, 18.3, 15.4,12.0, −3.4, −4.8, −5.2, −5.4, −5.7.

MS (ESI) m/z: 921 (M+23)⁺.

R_(f)=0.24 (Hex:EtOAc, 4:1).

Example 79 Compound 35b

To a solution of 14b (40 mg, 0.047 mmol) in acetone (1.5 mL) was addeddimethoxypropane (1.5 mL) and camphorsulfonic acid (1 mg, 0.0047 mmol)and the mixture was stirred for 1 h at 23° C. (until TLC revealed totalconsumption of the starting material). Et₃N (14 μL, 0.01 mmol) was thenadded and the mixture was stirred for 30 min. Solvents were removedunder reduced pressure and the mixture was subjected to flash columnchromatography on silica gel (Hex:EtOAc, 4:1) affording acetonide 35b(40 mg, 95%) as a colourless oil.

¹H NMR (300 MHz, CDCl₃) δ 7.25 (d, J=8.8 Hz, 2H), 6.87 (d, J=8.8 Hz,2H), 4.42 (dd, J=22.7, 11.3 Hz, 2H), 4.36-4.20 (m, 1H), 4.05 (d, J=11.5Hz, 1H), 3.80 (s, 3H), 3.82-3.74 (m, 1H), 3.70 (s, 3H), 3.52-3.42 (m,4H), 3.38-3.33 (m, 1H) 3.19 (s, 3H), 3.07 (d, J=8.0 Hz, 1H) 2.70 (br s,1H), 2.48 (d, J=8.6 Hz, 1H), 2.04-1.92 (m, 2H), 1.86-1.76 (m, 1H),1.28(s, 3H), 1.27 (s, 3H), 1.25 (s, 3H), 1.10 (d, J=6.7 Hz, 3H), 0.91 (s,9H), 0.90 (s, 9H), 0.87 (s, 9H), 0.15 (s, 3H), 0.09 (s, 3H), 0.07 (s,3H), 0.03 (s, 3H), 0.02 (s, 3H), 0.01 (s, 3H).

¹³CNMR (75 MHz, CDCl₃) δ 172.8, 159.4, 130.7, 129.4, 114.0, 97.7, 77.5,73.1, 72.6, 69.4, 67.7, 64.2, 63.9, 61.7, 61.4, 60.0, 55.5, 47.4, 42.7,33.3, 30.0, 29.9, 26.4, 26.3, 26.2, 20.2, 18.6, 18.4, 18.3, 15.3, 12.0,−3.4, −3.6, −4.8, −5.2, −5.4, −5.7.

MS (ESI) m/z: 921 (M+23)⁺.

R_(f)=0.27 (Hex:EtOAc, 4:1).

Example 80 Compound 36a

To a solution of 38a (26 mg, 0.035 mmol) in acetone (1 mL) was addeddimethoxypropane (1 mL) and camphorsulfonic acid (1 mg, 0.0047 mmol) andthe mixture was stirred for 1 h at 23° C. (until TLC revealed totalconsumption of the starting material). Et₃N (14 μL, 0.01 mmol) was thenadded and the mixture was stirred for 30 min. Solvents were removedunder reduced pressure and the mixture was subjected to flashchromatography on silica gel (Hex:EtOAc, 3:1) affording acetonide 36a(18 mg, 70%) as a colourless oil.

¹H NMR (300 MHz, CDCl₃) δ 7.20 (d, J=8.6 Hz, 2H), 6.87 (d, J=8.6 Hz,2H), 5.784-5.71 (m,1H), 5.11-4.97 (m, 2H), 4.41-4.30 (m, 2H), 4.12 (dd,J=7.0, 5.2 Hz, 1H), 3.96-3.90 (m, 1H), 3.81 (s, 3H), 3.68 (s, 3H),3.70-3-61 (m, 2H), 3.46-3.41 (m, 1H), 3.33 (d, J=6.7 Hz, 2H), 3.17 (s,3H), 2.82-2.74 (m, 1H), 2.56 (d, J=9.3 Hz, 1H), 2.54-2.49 (m, 1H),2.41-2.34 (m, 1H), 1.85-1.60 (m, 2H), 1.34 (s, 3H), 1.29 (s, 3H), 1.25(s, 3H), 1.07 (d, J=6.7 Hz, 3H), 0.94 (s, 9H), 0.86 (s, 9H), 0.12 (s,3H), 0.10 (s, 3H), 0.01 (s, 3H), 0.00 (s, 3H).

¹³C NMR (75 MHz, CDCl₃) δ 172.8, 159.4, 137.1, 130.5, 129.3, 118.7,114.0, 101.6, 73.1, 72.8, 68.9, 66.2, 65.2, 64.7, 61.4, 59.0, 55.5,53.5, 43.8, 33.8, 29.9, 26.5, 26.2, 25.0, 24.1, 18.7, 18.3, 15.3, 13.8,−4.1, −4.3, −5.0, −5.1.

MS (ESI) m/z: 802 (M+23)⁺, 780 (M+1)⁺.

R_(f)=0.18 (Hex:EtOAc, 4:1).

Example 81 Compound 36b

To a solution of 38b (34 mg, 0.046 mmol) in acetone (1 mL) were addeddimethoxypropane (1 mL) and camphorsulfonic acid (1 mg, 0.0047 mmol) andthe mixture was stirred for 1 h at 23° C. (until TLC revealed totalconsumption of the starting material). Et₃N (14 μL, 0.01 mmol) was thenadded and the reaction was stirred for 30 min at 23° C. Solvents wereremoved under reduced pressure and the mixture was subjected to flashcolumn chromatography on silica gel (Hex:EtOAc, 3:1) affording acetonide36b (33 mg, 92%) as a colourless oil.

¹H NMR (300 MHz, CDCl₃) δ 7.20 (d, J=8.6 Hz, 2H), 6.86 (d, J=8.6 Hz,2H), 5.95-6.08 (m, 1H), 5.02-5.25 (m, 2H), 4.42-4.53 (m, 1H), 4.38 (s,2H), 4.26-4.28 (m, 1H), 3.80 (s, 3H), 3.58-3.69 (m, 2H), 3.65 (s, 3H),3.41-3.46 (m, 1H), 3.32 (d, J=6.7 Hz, 2H), 3.14 (s, 3H), 2.59-2.67 (m,1H), 2.55 (d, J ═9.1 Hz, 1H), 2.31 (d, J=10.4 Hz, 1H), 2.17-2.29 (m,1H), 1.64-1.80 (m, 2H), 1.47 (s, 3H), 1.33 (s, 3H), 1.25 (s, 3H), 1.06(d, J=6.7 Hz, 3H), 0.92 (s, 9H), 0.86 (s, 9H), 0.11 (s, 3H), 0.08 (s,3H), 0.00 (s, 3H), −0.02 (s, 3H).

¹³C NMR (75 MHz, CDCl₃) δ 171.2, 159.4, 134.5, 130.6, 129.3, 113.9,99.5, 76.5, 73.0, 72.9, 69.2, 64.4, 61.4, 58.7, 55.4, 48.3, 45.5, 36.6,33.7, 30.1, 29.9, 26.3, 26.1, 19.7, 18.6, 15.2, 13.6, −4.3, −5.1, −5.2.

MS (ESI) m/z: 780.7 (M+1)⁺, 802.7 (M+23)⁺.

R_(f)=0.20 (Hex:EtOAc, 4:1).

Example 82 Compound 37

To a solution of diol 11a (300 mg, 0.47 mmol) in CH₂Cl₂ (10 mL) wasadded Dess-Martin periodinane (DMP) (0.24 g, 0.56 mmol) and the mixturewas stirred at 0° C. for 1 h and for additional 30 min at 23° C. Asaturated aqueous solution of NaHCO₃ (20 mL) was added and the mixturewas extracted with CH₂Cl₂ (2×20 mL). The combined organic layers weredried over Na₂SO₄, filtered and evaporated under reduced pressure. Theresidue 37 was used in the next step without further purification.

¹H-NMR (300 MHz, CDCl₃): δ 9.45 (d, J=2.6 Hz, 1H), 7.21 (d, J=8.6 Hz,2H), 6.87 (d, J=8.6 Hz, 2H), 5.75-5.84 (m, 1H), 5.19-5.37 (m, 2H),4.55-4.58 (m, 1H), 4.40 (s, 2H), 3.81 (s, 3H), 3.45-3.88 (m, 4H), 3.38(d, J=8.7 Hz, 2H), 3.15-3.20 (m, 1H), 2.55 (d, J=9.1 Hz, 1H), 1.67-1.84(m, 2H), 1.25 (s, 3H), 1.06 (d, J=6.5 Hz, 3H), 0.91 (s, 9H), 0.87 (s,9H), 0.16 (s, 3H), 0.10 (s, 3H), 0.05 (s, 3H), 0.04 (s, 3H).

MS (ESI) m/z: 659.7 (M+23).

R_(f)=0.56 (Hex:EtOAc, 4:1).

Example 83 Compounds 38a and 38b

To a solution of N-methoxy-N-methyl acetamide (0.158 mL, 1.41 mmol) indry THF (5 mL) at −78° C. was added lithium bis(trimethylsilyl)amide(1.41 mL, 1.0 M in THF, 1.41 mmol) and the reaction mixture was stirredfor 1 h at this temperature. Then, a solution of crude aldehyde 37 (0.47mmol) in THF (10 mL) was added over the previous solution and thereaction mixture was stirred for an additional 1 h at −78° C. Then, asaturated aqueous solution on NH₄Cl (30 mL) was added and the mixturewas extracted with EtOAc (3×50 mL). The combined organic layers weredried over Na₂SO₄, filtered and concentrated in vacuo. The residue waspurified by flash column chromatography on silica gel (Hex:EtOAc from5:1 to 1:1) to yield 38a and 38b (38:62) as colourless oils (146 mg, 42%overall yield for two steps from 11a).

38a: ¹H NMR (300 MHz, CDCl₃) δ 7.25(d, J=8.6 Hz, 2H), 6.87 (d, J=8.6 Hz,2H), 5.81-5.86 (m, 1H), 5.07-5.22 (m, 2H), 4.46-4.50 (m, 1H), 4.44 (dd,J=24.4 and 11.5 Hz, 2H), 4.05-4.16 (m, 1H), 3.65-3.94 (m, 3H), 3.79 (s,3H), 3.53 (d, J=4.7 H), 3.32-3.44 (m, 2H), 3.15-3.23 (m, 1H), 3.17 (s,3H), 2.68-2.75 (m, 1H), 2.62 (d, J=9.3 Hz, 1H), 2.18-2.24 (m, 1H),2.09-2.15 (m, 1H), 1.82-1.93 (m, 2H), 1.24 (s, 3H), 1.04 (d, J=6.7 Hz,3H), 0.91 (s, 9H), 0.86 (s, 9H), 0.14 (s, 3H), 0.08 (s, 3H), 0.04 (s,3H), 0.02 (s, 3H).

¹³C NMR (75 MHz, CDCl₃) δ 174.5, 159.3, 139.5, 136.4, 130.7, 129.3,118.9, 114.0, 77.0, 73.0, 72.7, 69.9, 68.4, 64.9, 64.2, 61.4, 61.3,55.4, 55.0, 48.7, 36.5, 33.8, 32.1, 29.9, 26.3, 26.0, 18.4, 18.1, 15.1,14.1, −4.2, −5.0, −5.1, −5.2.

MS (ESI) m/z: 740.5 (M+1)⁺, 762.6 (M+23)⁺.

R_(f)=0.08 (Hex:EtOAc, 4:1).

38b: ¹H NMR (300 MHz, CDCl₃): δ 7.23 (d, J=. 8.6 Hz, 2H), 6.85 (d, J=8.6Hz, 2H), 5.95-6.08 (m,1H), 5.04-5.30 (m, 2H), 4.43 (dd, J=11.8, 11.8 Hz,2H), 4.29-4.33 (m, 1H), 4.12 (br s, 1H), 3.78-3.89 (m, 2H), 3.79 (s,3H), 3.57-3.72 (m, 1H), 3.65 (s, 3H), 3.33-3.44 (m, 2H), 3.15 (s, 3H),2.59 (d, J=9.1 Hz, 1H), 2.46-2.62 (m, 1H), 1.73-1.89 (m, 2H), 1.24 (s,3H), 1.06 (d, J=6.7 Hz, 3H), 0.91 (s, 9H), 0.86 (s, 9H), 0.15 (s, 3H),0.08 (s, 3H), 0.04 (s, 3H), 0.03 (s, 3H).

¹³C NMR (75 MHz, CDCl₃) δ 171.4, 159.3, 135.4, 130.6, 129.4, 119.2,113.9, 77.6, 73.0, 72.8, 72.7, 70.3, 64.8, 64.3, 61.4, 60.8, 55.4, 52.8,47.4, 36.7, 33.6, 29.9, 26.3, 18.4, 18.2, 15.0, 14.0, −4.2, −5.0, −5.1,−5.2.

MS (ESI) m/z: 740.6 (M+1)⁺, 762.6 (M+23)⁺. R_(f)=0.10 (Hex:EtOAc, 4:1).

Example 84 Compound 39a

To a solution of 38a (106 mg, 0.143 mmol) in CH₂Cl₂ (8 ML) at 0° C. wasadded 2,6-lutidine (0.051 mL, 0.44 mmol) and TBSOTf (0.05 mL, 0.22 mmol)successively. The reaction mixture was stirred at this temperature for 1h. Aqueous solution of NaHCO₃ (20 mL) was then added and extracted withCH₂Cl₂ (2×20 mL). The combined organic layers were dried over Na₂SO₄,filtered and concentrated in vacuo. The residue was purified by flashcolumn chromatography on silica gel (Hex:EtOAc, 10:1) to obtain compound39a (79 mg, 65%) as a colourless oil.

¹H NMR (300 MHz, CDCl₃) δ 7.23 (d, J=8.6 Hz, 2H), 6.88 (d, J=8.6 Hz,2H), 5.82-5.94 (m,1H), 5.07-5.20 (m, 2H), 4.44 (dd, J=18.8, 11.9 Hz,1H), 4.37-4.41 (m, 2H), 3.91-3.95 (m, 1H), 3.80 (s, 3H), 3.67-3.79 (m,2H), 3.64 (s, 3H), 3.30-3.40 (m, 2H), 3.13 (s, 3H), 3.07 (d, J=4.4 Hz,1H), 2.66-2.76 (m, 1H), 2.59 (d, J=9.1 Hz, 1H), 2.47 (dd, J=15.6, 3.4Hz, 1H), 2.27-2.34 (m, 1H), 1.68-1.82 (m, 2H), 1.25 (s, 3H), 1.05 (d,J=6.7 Hz, 3H), 0.91 (s, 9H), 0.86 (s, 9H), 0.85 (s, 9H), 0.14 (s, 3H),0.05 (s, 3H), 0.03 (s, 3H), 0.02 (s, 3H).

¹³C NMR (75 MHz, CDCl₃) δ 172.5, 159.1, 135.8, 130.4, 129.0, 118,4,113.8, 76.7, 72.9, 72.6, 70.3, 69.0, 64.6, 61.4, 60.4, 56.0, 55.4, 47.3,33.8, 29.9, 26.4, 26.1, 26.0, 18.5, 18.3, 18.1, 15.2, 14.0, −4.1, −4.2,−4.5, −5.0, −5.1.

MS (ESI) m/z: 854.4 (M+1)⁺, 876.2 (M+23)⁺.

R_(f)=0.53 (Hex:EtOAc, 4:1).

Example 85 Compound 39b

To a solution of 38b (89 mg, 0.12 mmol) in CH₂Cl₂ (8 mL) at 0° C. wasadded 2,6-lutidine (0.042 mL, 0.36 mmol) and TBSOTf (0.041 mL, 0.18mmol) successively. The reaction mixture was stirred at this temperaturefor 1 h. A saturated aqueous solution of NaHCO₃ (20 mL) was then addedand the mixture was extracted with CH₂Cl₂ (2×20 mL). The combinedorganic layers were dried over Na₂SO₄, filtered and concentrated invacuo. The residue was purified by flash column chromatography on silicagel (Hex:EtOAc, 10:1) to obtain compound 39b (86 mg, 84%) as acolourless oil.

¹H NMR (300 MHz, CDCl₃) δ 7.24 (d, J=8.6 Hz, 2H), 6.87 (d, J=8.6 Hz,2H), 5.89-6.01 (m, 1H), 5.03-5.25 (m, 2H), 4.40 (dd, J=18.4, 11.4 Hz,2H), 4.16-4.22 (m, 3H), 3.79-3.86 (m, 1H), 3.79 (s, 3H), 3.63-3.70 (m,1H), 3.67 (s, 3H), 3.27-3.44 (m, 3H), 3.16 (s, 3H), 2.70-2.80 (m, 1H),2.6 (d, J=9.1 Hz, 1H), 2.51-2.58 (m, 1H), 2.72-2.32 (m 1H), 1.65-1.89(m, 2H), 1.26 (s, 3H), 1.09 (d, J=6.7 Hz, 3H), 0.92 (s, 9H), 0.86 (s,9H), 0.13 (s, 3H), 0.10 (s, 3H), 0.09 (s, 3H), 0.06 (s, 3H), 0.04 (s,3H), 0.03 (s, 3H).

¹³C NMR (75 MHz, CDCl₃) δ 172.7, 159.4, 137.5, 130.5, 129.5, 118.5,114.0, 76.4, 73.1, 72.7, 69.1, 64.8, 64.1, 61.5, 61.0, 55.4, 54.4, 44.4,37.3, 34.4, 32.1, 29.9, 26.6, 26.2, 26.0, 18.9, 18.2, 17.9, 15.4, 12.7,−4.0, −4.2, −4.7, −5.0, −5.1.

MS (ESI) m/z: 854.4 (M+1)⁺, 876.3 (M+23)⁺.

R_(f)=0.43 (Hex:EtOAc, 4:1).

Example 86 Compound 40a

Over a solution of 39a (79 mg, 0.09 mmol) in CH₂Cl₂ (15 mL) at −78° C.was bubbled ozone until the clear solution turned to light blue (2 min).Then MeOH (15 mL) and NaBH₄ (15 mg, 0.4 mmol) were added and thesolution was allowed to reach 23° C. during 2 h. After this time,solvents were removed under reduced pressure, an the residue wasdissolved in CH₂Cl₂, hydrolysed with aqueous NH₄Cl and extracted withCH₂Cl₂ (2×20 mL). The combined organic layers were dried over Na₂SO₄,filtered and concentrated in vacuo. The residue was purified by flashcolumn chromatography on silica gel (Hex:EtOAc, from 4:1 to 2:1) toobtain compound 40a (10 mg, 13%) as a colourless oil.

¹H NMR (300 MHz, CDCl₃) δ 7.23 (d, J=8.6 Hz, 2H), 6.89 (d, J=8.6 Hz,2H), 4.43 (dd, J=19.6, 11.7 Hz, 2H), 4.20-4.33 (m, 2H), 3.61-4-07 (m,5H), 3.81 (s, 3H), 3.68 (s, 3H), 3.31-3.45 (m, 2H), 3.16 (s, 3H),2.77-2.89 (m, 1H), 2.65 (d, J=9.3 Hz, 1H), 2.03-2.16 (m, 2H), 1-76-1.81(m, 2H), 1.62-1.68 (m, 2H), 1.25 (s, 3H), 1.07 (d, J=6.5 Hz, 3H), 0.90(s, 9H), 0.88 (s, 9H), 0.86 (s, 9H), 0.15 (s, 3H), 0.12 (s, 3H), 0.11(s, 3H), 0.10 (s, 3H), 0.08 (s, 3H), 0.00 (s, 3H).

MS (ESI) m/z: 880 (M+23)⁺.

R_(f)=0.15 (Hex:EtOAc, 4:1).

Example 87 Compound 40b

Over a solution of 39b (86 mg, 0.1 mmol) in CH₂Cl₂ (15 mL) at −78° C.was bubbled ozone until the clear solution turned to light blue (2 min).Then MeOH (15 mL) and NaBH₄ (15 mg, 0.4 mmol) were added and thesolution was allowed to reach room temperature during 2 h. After thistime, solvents were removed under reduced pressure, and the residue wasdissolved in CH₂Cl₂, hydrolysed with aqueous NH₄Cl and extracted withCH₂Cl₂ (2×20 mL). The combined-organic layers were dried over Na₂SO₄,filtered and concentrated in vacuo. The residue was purified by flashcolumn chromatography on silica gel (Hex:EtOAc, from 4:1 to 2:1) toobtain compound 40b (50 mg, 58%) as a colourless oil.

¹H NMR (300 MHz, CDCl₃): δ 7.25 (d, J=8.6 Hz, 2H), 6.87 (d, J=8.6 Hz,2H), 4.41 (dd, J=19.3, 11.4 Hz, 2H), 4.18-4.40 (m, 3H), 3.64-3.95 (m,6H), 3.79 (s, 3H), 3.71 (s, 3H), 3.30-3.42 (m, 2H), 3.16 (s, 3H),2.90-2.98 (m, 1H), 2.60 (d, J=9.1 Hz, 1H), 2.55-2.62 (m, 1H), 1.78-1.87(m, 3H), 1.27 (s, 3H), 1.08 (d, J=6.7 Hz, 3H), 0.92 (s, 9H), 0.86 (s.,9H), 0.85 (s, 9H), 0.14 (s, 3H), 0.12 (s, 3H), 0.09 (s, 3H), 0.05 (s, 3H), 0.05 (s, 3H), 0.03 (s, 3H).

¹³C NMR (75 MHz, CDCl₃) δ 171.8, 159.2, 130.2, 129.4, 113.8, 75.8, 72.8,72.5, 72.2, 68.7, 64.5, 63.6, 63.2, 61.4, 60.7, 55.2, 48.5, 43.0, 37.4,34.2, 31.9, 29.7, 26.3, 25.9, 25.7, 18.6, 17.9, 17.6, 15.2, 12.5, −4.4,−4.5, −5.1, .5.2, −5.4, −5.5.

MS (ESI) m/z: 880 (M+23)⁺.

R_(f)=0.13 (Hex:EtOAc, 4:1).

Example 88 Compound 41b

To a solution of 40b (50 mg, 0.06 mmol) in CH₂Cl₂ (8 mL) at 0° C. wasadded 2,6-lutidine (0.021 mL, 0.18 mmol) and TBSOTf (0.021′ mL, 0.09mmol) successively. The reaction mixture was stirred at this temperaturefor 1 h. A saturated aqueous solution of NaHCO₃ (20 mL) was then addedand the mixture was extracted with CH₂Cl₂ (2×20 mL). The combinedorganic layers were dried over Na₂SO₄, filtered and concentrated invacuo. The residue was purified by flash column chromatography on silicagel (Hex:EtOAc, 10:1) to obtain compound 41b (57 mg, 98%) as acolourless oil.

¹H NMR (300 MHz, CDCl₃) δ 7.23 (d, J=8.6 Hz, 2H), 6.87 (d, J=8.6 Hz,2H), 4.65 (m, 1H), 4.41 (dd, J=15.9, 11.7 Hz, 2H), 4.17-4.21 (m, 1H),4.04-4.11 (m, 2H), 3.79-3.86 (m, 1H), 3.80 (s, 3H), 3.66 (s, 3H),3.25-3.31 (m, 1H), 3.16 (s, 3H), 2.72-2.84 (m, 1H), 2.62 (d, J=9.3 Hz,1H1), 2.46-2.54 (m, 1H), 1.82-2.05 (m, 1H), 1.62-1.82 (m, 2H), 1.25 (s,3H), 1.10 (d, J=6.7 Hz, 3H), 0.92 (s, 9H), 0.91 (s, 9H), 0.87 (s, 9H),0.83 (s, 9H), 0.16 (s, 3H), 0.11 (s, 3H), 0.10 (s, 3H), 0.08 (s, 3H),0.07 (s, 3H), 0.05 (s, 3H), 0.03 (s, 3H).

¹³C NMR (75 MHz, CDCl₃) δ 173.1, 159.4, 130.0, 129.4, 114.0, 76.2, 72.8,72.0, 69.2, 68.7, 64.5, 63.7, 61.9, 61.5, 55.4, 51.2, 44.5, 34.4, 29.9,26.5, 26.2, 26.1, 18.8, 18.4, 18.1, 17.9, 15.6, 12.3, −3.8, −4.6, −4.7,−5.0, −5.1, −5.2.

MS (ESI) m/z: 972.6 (M+1)⁺, 994.6 (M+23)⁺.

R=0.56 (Hex:EtOAc, 4:1).

Example 89 Compounds 43 and 44

To a solution of 20b (14 mg, 0.024 mmol) in CHCl₃ (3 mL) was added Et₃N(28 μL, 0.2 mmol) and Ac₂O (10 μL, 0.1 mmol) at 23° C. The reactionmixture was stirred at 23° C. for 16 h. Then, the solvent was eliminatedunder reduced pressure and the residue was purified by flash columnchromatography on silica gel (Hex:EtOAc, from 2:1 to 1:1) to obtain purecompounds 43 (6 mg, 47%) as a yellow oil and 44 (6 mg, 44%) as a whitesolid.

43: ¹H NMR (300 MHz, CDCl₃) (data of the mayor product) δ 5.53-5.45 (m,1H), 5.31-5.19 (m, 1H), 4.45-4.40 (m, 2H), 3.92-3.80 (m, 3H), 3.53 (d,J=9.9 Hz, 1H), 3.27-3.21 (m, 1H), 2.76-2.66 (m, 1H), 2.56 (d, J=9.3 Hz,1H),2.49-2.41 (m, 1H), 2.06-2.00 (m, 1H), 2.03 (s, 3H), 1.68-1.66 (m,3H), 1.62 (dd, J=12.0, 6.6 Hz, 3H), 1.32 (s, 3H), 1.13 (d, J=6.6 Hz,3H), 0.97 (t, J=7.5 Hz, 3H), 0.86 (s, 9H), 0.13 (s, 3H), −0.01 (s, 3H),

MS (ESI) m/z: 551 (M+23)⁺.

Rf=0.39 (Hex:EtOAc, 50:50).

44: ¹H NMR (300 MHz, CDCl₃) δ 5.52-5.46 (m, 1H), 5.22-5.15 (m, 1H), 4.50(dd, J=11.0, 4.5 Hz, 1H), 4.47-4.43 (m, 1H), 4.34-4.33 (m, 1H) 4.13-4.07(m, 1H), 3.90-3.81 (m, 1H), 3.70-3.65 (m, 1H), 3.56 (d, J=9.3 Hz, 1H),3.33-3.26 (m, 1H), 3.13-3.11 (m, 1H), 2.69-2.64 (m, 2H), 2.55 (d, J=9.0Hz, 1H),2.48-2.39 (m, 2H), 2.09 (s, 3H), 1.67-1.61 (m, 3H), 1.32 (s,3H), 1.13 (d, J=6.3 Hz, 3H), 1.05 (t, J=7.2 Hz, 3H), 0.85 (s, 9H), 0.15(s, 3H), −0.01 (s, 3H).

MS (ESI) m/z: 593 (M+23)⁺.

Rf=0.53 (Hex:EtOAc, 50:50).

Example 90 Compound 45

To a solution of 20b (34 mg, 0.07 mmol) in CH₂Cl₂ (0.7 mL) was addedEt₃N (11.5 μL, 0.82 mmol), DMAP (5 mg, 0.041 mmol) and Ac₂O (39 μL, 0.41mmol) at 0° C. The reaction mixture was stirred at 23° C. for 3 h. Then,0.1N HCl was added until pH=4-5, and the reaction was extracted withCH₂Cl₂ (2×5 mL). The combined organic layers were dried over Na₂SO₄,filtered, and concentrated under reduced pressure. The residue waspurified by flash column chromatography on silica gel (Hex:EtOAc, 3:1)to obtain compound 45 (17 mg, 40%) as a yellow oil.

¹H NMR (300 MHz, CDCl₃) δ 5.60-5.56 (m, 1H), 5.54-5.44 (m, 1H),5.26-5.19 (m, 1H), 4.46 (dd, J=11.1, 5.7 Hz, 1H), 4.35 (dd, J=11.4, 3.3Hz, 1H), 4.14 (dd, J=12.0, 6.9 Hz, 1H), 3.87 (dd, J=11.4, 8.1 Hz, 1H),3.55-3.49 (m, 2H), 3.46-3.38 (m, 2H), 2.79-2.76 (m, 2H), 2.52 (d, J=9.3Hz, 1H),2.45-2.38 (m, 3H), 2.06 (s, 3H), 1.99 (s, 6H), 1.62 (dd, J=6.9,1.8 Hz, 1H), 1.33 (s, 3H), 1.11 (d, J=6.3 Hz, 3H), 1.03 (t, J=7.2 Hz,3H), 0.85 (s, 9H), 0.13 (s, 3H), 0.00 (s, 3H).

MS (ESI) m/z: 635 (M+23)⁺.

Rf=0.54 (Hex:EtOAc, 50:50).

Example 91 Compound 46

To a solution of 20a (18 mg, 0.037 mmol) in CH₂Cl₂ (3 ML) was added Et₃N(21 μL, 0.15 mmol) and Ac₂O (7 μL, 0.074 mmol) at 23° C. The reactionmixture was stirred at 23° C. for 16 h. Then, NaHCO₃ (5 mL) was addedand the reaction was extracted with CH₂Cl₂ (2×5 mL). The combinedorganic layers were dried over Na₂SO₄, filtered, and concentrated underreduced pressure. The residue was purified by flash columnchromatography on silica gel (Hex:EtOAc, from 3:1 to 2:1) to obtaincompound 46 (16 mg, 82%) as a white solid.

¹H NMR (300 MHz, CDCl₃) (data of the mayor product) δ 5.55-5.45 (m, 1H),5.26-5.19 (m, 1H), 5.06 (s, 1H), 4.56 (bs, 1H), 4.45 (dd, J=11.4, 3.6Hz, 1H), 4.22 (t, J=11.7 Hz, 1H), 4.06 (bs, 1H), 3.97-3.82 (m, 2H), 3.47(d, J=9.6 Hz, 1H), 3.21-3.14 (m, 1H), 2.94-2.89 (m, 1H), 2.56 (d, J=9.0Hz, 1H),2.06-2.98 (m, 1H), 2.02 (s, 3H), 1.63-1.58 (m, 6H), 1.30 (s,3H), 1.13 (d, J=6.6 Hz, 3H), 0.94 (t, J=7.5 Hz, 3H), 0.85 (s, 9H), 0.13(s, 3H), −0.01 (s, 3H).

¹³C NMR (75 MHz, CDCl₃) (data of the mayor product) δ 212.2, 170.4,130.5, 125.3, 97.5, 77.5, 66.0, 65.6, 62.2, 62.1, 55.9, 54.2, 54.1,37.4, 34.6, 31.6, 29.9, 26.2, 20.9, 18.9, 13.5, 11.8, 7.7, −4.2, −4.6.

MS (ESI) m/z: 551 (M+23)⁺.

Rf=0.38 (Hex:EtOAc, 2:1).

Example 92 Compounds 47 and 1

To a solution of crude 4a (20 mg, 0.054 mmol) in CHCl₃ (3 mL) was addedEt₃N (22 μL, 0.16 mmol) and Ac₂O (8 μL, 0.081 mmol) at 23° C. Thereaction mixture was stirred at 23° C. for 16 h. Then, the solvent waseliminated under reduced pressure and the residue was purified by flashcolumn chromatography on silica gel (Hex:EtOAc, from 2:1 to 1:1) toobtain pure compounds 47 (10 mg, 48%) and 1 (4 mg, 44%) as yellow oils.

47: ¹H NMR (500 MHz CD₃OD) (data of the hemiketal product) δ 5.50 (m,1H), 5.26 (m, 1H), 4.57 (m, 1H), 4.28 (dd, J=12.5, 12.0 Hz, 1H),.4.15(dd, J=11.0, 4.0 Hz, 1H), 4.00 (dd, J=11.0, 9.5 Hz, 1H), 3.69 (dd,J=12.5, 5.0 Hz, 1H), 3.40 (m, 1H), 3.13 (d, J=10.5 Hz, 1H), 2.97 (ddd,J=12.0, 5.0, 2.5 Hz, 1H), 2.62 (d, J=9.5 Hz, 1H), 2.47 (m, 1H), 1.97 (s,3H), 1.93 (dd, J=14.0, 3.0 Hz, 1H), 1.72 (dd, J=14.0, 3.0 Hz, 1H), 1.64(brd, J=7.0 Hz, 3H), 1.57 (d, J=7.5 Hz, 2H), 1.37 (s, 3H), 1.09 (d,J=7.0 Hz, 3 H), 0.92 (t, J=7.5 Hz, 3H).

¹³C NMR (125 MHz CD₃OD) (data of the hemiketal product) δ 212.6, 172.6,131.5, 126.1, 98.8, 78.6, 67.6, 66.1, 64.3, 62.9, 56.8, 56.0, 52.2,38.6, 35.6, 32.3, 20.8, 18.8, 13.6, 11.6, 7.9.

MS (ESI) m/z: 437 (M+23)⁺.

1: ¹H NMR (500 MHz MeOD) δ 6.27 (s, 1H), 6.22 (d, J=1.2 Hz, 1H),5.55-5.46 (m, 1H), 5.30-5.23 (m, 1H), 5.04-5.01 (m, 1H), 4.32 (dd,J=10.5, 3.9 Hz, 1H), 3.88 (dd, J=9.9, 9.9 Hz, 1H), 3.76 (ddd, J=19.8,9.9, 3.6 Hz 1H), 3.34 (d, J=9.9 Hz), 1.94 (s, 3H), 1.65 (dd, J=6.9, 1.8Hz, 1H), 1.38 (d, J=6.6 Hz, 3H), 1.01 (t, J=7.5 Hz, 3H).

MS (ESI) m/z: 419 (M+23)⁺.

Rf=0.37 (Hex:EtOAc, 1:2).

Example 93 Bioassays for Antitumor Screening

The finality of these assays is to interrupt the growth of a “in vitro”tumor cell culture by means a continued exhibition of the cells to thesample to be testing.

Cell Lines N° NAME ATCC SPECIES TISSUE CHARACTERISTICS K-562 CCL-243human leukemia erythroleukemia (pleural effusion) A-549 CCL-185 humanlung lung carcinoma “NSCL” SK-MEL- HTB-72 human melanoma malignantmelanoma 28 HT-29 HTB-38 human colon colon adenocarcinoma LoVo CCL-229human colon colon adenocarcinoma LoVo-Dox human colon colonadenocarcinoma (MDR) DU-145 HTB-81 human prostate prostate carcinoma,not androgen receptors LNCaP CRL-1740 human prostate prostateadenocarcinoma, with androgen receptors SK-BR-3 HTB-30 human breastbreast adenocarcinoma, Her2/neu+, (pleural effusion) IGROV human ovaryovary adenocarcinoma IGROV- human ovary ovary adenocarcinoma, ETcharacterized as ET-743 resistant cells HeLa CCL-2 human cervix cervixepitheloid carcinoma HeLa- CCL-3 human cervix cervix epitheloid APLcarcinoma, characterized as aplidine resistant cells PANC-1 CRL-1469human pancreas pancreatic epitheloid carcinomaInhibition of Cell Growth by Colorimetric Assay.

A colorimetric type of assay, using sulforhodamine B (SRB) reaction hasbeen adapted for a quantitative measurement of cell growth and viability(following the technique described by P. A. Skehan, et al., J. Natl.Cancer Inst. 1990, 82, 1107-1112).

This form of assay employs 96 well cell culture microplates of 9 mmdiameter (T. Mosmann et al., J. of Immunological Methods 1983, 65,55-63; G. T. Faircloth et al., J. of Tissue and Culture Methods 1988,11, 201-205). Most of the cell lines are obtained from American TypeCulture Collection (ATCC) derived from different human cancer types.

Cells are maintained in RPMI 1640 10% FBS, supplemented with 0.1 g/Lpenicillin and 0.1 g/L streptomycin sulfate and then incubated at 37°C., 5% CO₂ and 98% humidity. For the experiments, cells were harvestedfrom subconfluent cultures using trrpsin and resuspended in fresh mediumbefore plating.

Cells are seeded in 96 well microtiter plates, at 5×10³ cells per wellin aliquots of 195 μL medium, and they are allowed to attach to theplate surface by growing in drug free medium for 18 hours. Afterward,samples are added in aliquots of 5 μL in a ranging from 10 to 10⁻⁸μg/mL, dissolved in DMSO/EtOH/PBS (0.5:0.5:99). After 48 hours exposure,the antitumor effect are measured by the SRB methodology: cells arefixed by adding 50 μL of cold 50% (wt/vol) trichloroacetic acid (TCA)and incubated for 60 minutes at 4° C. Plates are washed with deionisedwater and dried. One hundred μl of SRB solution (0.4% wt/vol in 1%acetic acid) is added to each microtiter well and incubated for 10minutes at room temperature. Unbound SRB is removed by washing with 1%acetic acid. Plates are air dried and bound stain is solubilized withTris buffer. Optical densities are read on a automatedspectrophotometric plate reader at a single wavelength of 490 nm.

The values for mean±SD of data from triplicate wells are calculated.Some parameters for cellular responses can be calculated: GI=growthinhibition, TGI=total growth inhibition (cytostatic effect) and LC=cellkilling (cytotoxic effect).

Tables 1 illustrates data on the biological activity of the compounds ofthe present invention. TABLE 1 Activity data (Molar) 19a 19b 20a + 20c20b + 20d 31b + 31d DU-145 GI50 1.21E−05 1.20E−05 1.07E−05 2.05E−052.05E−05 TGI 1.21E−05 1.20E−05 2.05E−05 2.05E−05 2.05E−05 LC50 1.21E−051.20E−05 2.05E−05 2.05E−05 2.05E−05 LN-caP GI50 1.21E−05 1.20E−058.42E−06 1.24E−05 — TGI 1.21E−05 1.20E−05 2.05E−05 2.05E−05 — LC501.21E−05 1.20E−05 2.05E−05 2.05E−05 — IGROV GI50 1.21E−05 1.20E−051.41E−05 2.05E−05 1.65E−05 TGI 1.21E−05 1.20E−05 2.05E−05 2.05E−052.05E−05 LC50 1.21E−05 1.20E−05 2.05E−05 2.05E−05 2.05E−05 IGROV-ET GI501.21E−05 1.20E−05 1.38E−05 2.05E−05 2.05E−05 TGI 1.21E−05 1.20E−052.05E−05 2.05E−05 2.05E−05 LC50 1.21E−05 1.20E−05 2.05E−05 2.05E−052.05E−05 SK-BR-3 GI50 1.21E−05 6.15E−06 1.11E−05 1.49E−05 2.02E−05 TGI1.21E−05 1.17E−05 2.05E−05 2.05E−05 2.05E−05 LC50 1.21E−05 1.20E−052.05E−05 2.05E−05 2.05E−05 MEL-28 GI50 1.21E−05 1.20E−05 1.63E−052.05E−05 2.05E−05 TGI 1.21E−05 1.20E−05 2.05E−05 2.05E−05 2.05E−05 LC501.21E−05 1.20E−05 2.05E−05 2.05E−05 2.05E−05 A-549 GI50 1.21E−051.20E−05 2.05E−05 2.05E−05 2.05E−05 TGI 1.21E−05 1.20E−05 2.05E−052.05E−05 2.05E−05 LC50 1.21E−05 1.20E−05 2.05E−05 2.05E−05 2.05E−05K-562 GI50 1.21E−05 1.20E−05 7.75E−06 1.03E−05 — TGI 1.21E−05 1.20E−052.05E−05 2.05E−05 — LC50 1.21E−05 1.20E−05 2.05E−05 2.05E−05 — PANC-1GI50 1.21E−05 1.20E−05 1.40E−05 9.37E−06 1.26E−05 TGI 1.21E−05 1.20E−052.05E−05 2.05E−05 2.05E−05 LC50 1.21E−05 1.20E−05 2.05E−05 2.05E−052.05E−05 HT-29 GI50 1.21E−05 1.20E−05 1.71E−05 2.05E−05 2.05E−05 TGI1.21E−05 1.20E−05 2.05E−05 2.05E−05 2.05E−05 LC50 1.21E−05 1.20E−052.05E−05 2.05E−05 2.05E−05 LOVO GI50 1.21E−05 1.20E−05 1.04E−05 2.05E−052.05E−05 TGI 1.21E−05 1.20E−05 2.05E−05 2.05E−05 2.05E−05 LC50 1.21E−051.20E−05 2.05E−05 2.05E−05 2.05E−05 LOVO-DOX GI50 1.21E−05 1.20E−058.51E−05 2.05E−05 2.05E−05 TGI 1.21E−05 1.20E−05 2.05E−05 2.05E−052.05E−05 LC50 1.21E−05 1.20E−05 2.05E−05 2.05E−05 2.05E−05 HELA GI501.21E−05 1.20E−05 1.33E−05 2.05E−05 2.05E−05 TGI 1.21E−05 1.20E−052.05E−05 2.05E−05 2.05E−05 LC50 1.21E−05 1.20E−05 2.05E−05 2.05E−052.05E−05 HELA-APL GI50 1.21E−05 1.20E−05 1.29E−05 2.05E−05 2.05E−05 TGI1.21E−05 1.20E−05 2.05E−05 2.05E−05 2.05E−05 LC50 1.21E−05 1.20E−052.05E−05 2.05E−05 2.05E−05 30a 30b 3a + 4a 3b + 4b 3c + 4c 3d + 4dDU-145 GI50 1.21E−05 1.21E−05 6.31E−08 6.52E−06 5.50E−07 2.68E−05 TGI1.21E−05 1.21E−05 4.03E−07 2.68E−05 4.16E−06 2.68E−05 LC50 1.21E−051.21E−05 2.03E−06 2.68E−05 2.68E−05 2.68E−05 LN-caP GI50 — — 8.19E−089.29E−06 7.03E−07 — TGI — — 5.53E−07 2.68E−05 4.56E−06 — LC50 — —5.32E−06 2.68E−05 2.68E−05 — IGROV GI50 — — 7.30E−08 5.96E−06 5.53E−072.05E−05 TGI — — 3.76E−07 2.68E−05 3.57E−06 2.68E−05 LC50 — — 3.92E−062.68E−05 2.09E−05 2.68E−05 IGROV-ET GI50 8.27E−06 8.27E−06 1.00E−076.55E−06 7.03E−07 1.71E−05 TGI 1.21E−05 1.21E−05 1.07E−06 2.68E−056.95E−06 2.68E−05 LC50 1.21E−05 1.21E−05 2.68E−05 2.68E−05 2.68E−052.68E−05 SK-BR-3 GI50 8.56E−06 1.21E−05 3.03E−08 5.07E−06 1.16E−062.05E−05 TGI 1.21E−05 1.21E−05 4.75E−07 1.09E−05 6.07E−06 2.68E−05 LC501.21E−05 1.21E−05 5.34E−06 2.33E−05 2.68E−05 2.68E−05 MEL-28 GI501.21E−05 1.21E−05 7.54E−08 5.53E−06 6.34E−07 2.68E−05 TGI 1.21E−051.21E−05 8.32E−07 2.68E−05 7.25E−06 2.68E−05 LC50 1.21E−05 1.21E−051.20E−05 2.68E−05 2.68E−05 2.68E−05 A-549 GI50 1.21E−05 1.21E−051.44E−07 2.68E−05 9.13E−07 2.68E−05 TGI 1.21E−05 1.21E−05 2.59E−062.68E−05 1.34E−05 2.68E−05 LC50 1.21E−05 1.21E−05 1.56E−05 2.68E−052.68E−05 2.68E−05 K-562 GI50 — — 5.21E−07 1.42E−05 4.59E−06 — TGI — —1.46E−06 1.82E−05 1.19E−05 — LC50 — — 8.40E−06 2.33E−05 2.68E−05 —PANC-1 GI50 1.21E−05 1.21E−05 8.97E−08 2.68E−05 1.03E−06 1.35E−05 TGI1.21E−05 1.21E−05 2.95E−06 2.68E−05 1.33E−05 2.68E−05 LC50 1.21E−051.21E−05 2.68E−05 2.68E−05 2.68E−05 2.68E−05 HT-29 GI50 — — 6.01E−082.21E−05 5.64E−07 2.68E−05 TGI — — 1.18E−06 2.68E−05 6.69E−06 2.68E−05LC50 — — 2.68E−05 2.68E−05 2.68E−05 2.68E−05 LOVO GI50 6.37E−06 6.88E−068.22E−08 4.81E−06 7.14E−07 2.68E−05 TGI 1.21E−05 1.21E−05 1.35E−061.26E−05 7.01E−06 2.68E−05 LC50 1.21E−05 1.21E−05 1.77E−05 2.68E−052.68E−05 2.68E−05 LOVO-DOX GI50 1.21E−05 1.21E−05 1.52E−07 9.34E−068.46E−07 2.68E−05 TGI 1.21E−05 1.21E−05 1.36E−06 2.68E−05 6.18E−062.68E−05 LC50 1.21E−05 1.21E−05 2.68E−05 2.68E−05 2.68E−05 2.68E−05 HELAGI50 1.21E−05 1.21E−05 7.28E−08 8.73E−06 6.20E−07 2.68E−05 TGI 1.21E−051.21E−05 5.50E−07 2.68E−05 4.78E−06 2.68E−05 LC50 1.21E−05 1.21E−057.14E−06 2.68E−05 2.68E−05 2.68E−05 HELA-APL GI50 1.21E−05 1.21E−057.33E−08 5.18E−06 5.93E−07 2.68E−05 TGI 1.21E−05 1.21E−05 9.83E−072.68E−05 8.67E−06 2.68E−05 LC50 1.21E−05 1.21E−05 1.47E−05 2.68E−052.68E−05 2.68E−05 46 43 44 45 47 1 DU-145 GI50 9.65E−06 4.99E−064.99E−06 1.63E−05 8.15E−08 3.66E−06 TGI 1.89E−05 9.66E−06 1.04E−051.63E−05 5.31E−07 1.02E−05 LC50 1.89E−05 1.87E−05 1.75E−05 1.63E−052.41E−05 2.52E−05 LN-caP GI50 5.24E−06 3.78E−06 3.77E−06 8.34E−068.13E−08 1.45E−06 TGI 9.06E−06 7.62E−06 7.88E−06 1.63E−05 5.36E−076.31E−06 LC50 1.56E−05 1.54E−05 1.66E−05 1.63E−05 8.88E−06 2.52E−05IGROV GI50 7.74E−06 4.94E−06 4.13E−06 1.63E−05 6.39E−08 1.63E−06 TGI1.89E−05 9.99E−06 7.67E−06 1.63E−05 5.28E−07 5.67E−06 LC50 1.89E−051.89E−05 1.42E−05 1.63E−05 2.41E−05 1.76E−05 IGROV-ET GI50 7.39E−064.52E−06 4.15E−06 1.58E−05 1.52E−07 3.10E−06 TGI 1.89E−05 8.96E−068.09E−06 1.63E−05 1.08E−06 8.58E−06 LC50 1.89E−05 1.78E−05 1.58E−051.63E−05 2.41E−05 2.37E−05 SK-BR-3 GI50 — — — — 2.31E−08 4.69E−07 TGI —— — — 1.18E−07 1.11E−05 LC50 — — — — 2.30E−06 3.43E−06 MEL-28 GI509.89E−06 3.90E−06 3.84E−06 1.63E−05 8.20E−08 2.72E−06 TGI 1.89E−057.24E−06 6.96E−06 1.63E−05 9.84E−07 6.10E−06 LC50 1.89E−05 1.34E−051.26E−05 1.63E−05 1.29E−05 1.36E−05 A-549 GI50 1.34E−05 4.44E−064.01E−06 1.63E−05 1.51E−07 1.10E−06 TGI 1.89E−05 8.49E−06 7.87E−061.63E−05 1.12E−06 5.04E−06 LC50 1.89E−05 1.62E−05 1.54E−05 1.63E−052.32E−05 2.35E−05 K-562 GI50 1.20E−05 3.59E−06 6.10E−06 1.63E−052.94E−07 1.99E−06 TGI 1.89E−05 7.72E−06 1.14E−05 1.63E−05 9.99E−077.36E−06 LC50 1.89E−05 1.65E−05 1.75E−05 1.63E−05 1.18E−05 2.46E−05PANC-1 GI50 7.38E−06 3.73E−06 3.73E−06 8.24E−06 9.05E−08 3.33E−06 TGI1.89E−05 7.02E−06 7.20E−06 1.63E−05 2.38E−06 8.40E−06 LC50 1.89E−051.32E−05 1.38E−05 1.63E−05 1.95E−05 2.13E−05 HT-29 GI50 1.50E−054.24E−06 6.22E−06 1.63E−05 1.06E−07 1.67E−06 TGI 1.89E−05 8.28E−061.75E−05 1.63E−05 3.11E−06 5.37E−06 LC50 1.89E−05 1.62E−05 1.70E−051.63E−05 2.41E−05 1.34E−05 LOVO GI50 4.37E−06 4.03E−06 4.05E−06 8.26E−064.03E−08 1.62E−06 TGI 1.00E−05 9.06E−06 8.99E−06 1.63E−05 3.74E−074.87E−06 LC50 1.89E−05 1.89E−05 1.75E−05 1.63E−05 1.77E−05 1.26E−05LOVO-DOX GI50 6.15E−06 3.31E−06 4.27E−06 1.05E−05 2.16E−07 3.13E−06 TGI1.89E−05 7.21E−06 8.90E−06 1.63E−05 2.41E−05 8.10E−06 LC50 1.89E−051.57E−05 1.75E−05 1.63E−05 2.41E−05 2.11E−05 HELA GI50 8.81E−06 4.37E−063.91E−06 1.63E−05 7.17E−08 1.99E−06 TGI 1.89E−05 8.47E−06 7.59E−061.63E−05 4.34E−07 6.66E−06 LC50 1.89E−05 1.64E−05 1.47E−05 1.63E−051.35E−05 2.05E−05 HELA-APL GI50 1.01E−05 4.27E−06 3.77E−06 1.63E−057.96E−08 1.72E−06 TGI 1.89E−05 9.34E−06 9.83E−06 1.63E−05 5.91E−076.23E−06 LC50 1.89E−05 1.89E−05 1.75E−05 1.63E−05 2.41E−05 2.20E−03

1. A compound of the general formula I or a pharmaceutically acceptablesalt, derivative, prodrug or stereoisomer thereof

wherein the substituent groups defined by R are each independentlyselected from the group consisting of H, SiR′₃, SOR′, SO₂R′, C(═O)R′,C(═O)OR′, C(═O)NR′, substituted or unsubstituted alkyl, substituted orunsubstituted alkenyl, substituted or unsubstituted alkynyl, aryl,heteroaryl or aralkyl; the group R′ is selected from substituted orunsubstituted alkyl, substituted or unsubstituted alkenyl, substitutedor unsubstituted alkynyl, aminoalkyl, aryl, aralkyl and heterocyclicgroups; and the group R″ is selected from the group consisting of H, OH,OR′, OCOR′, SH, SR′, SOR′, SO₂R′, NO₂, NH₂, NHR′, N(R′)₂, NHCOR′,N(COR′)₂, NHSO₂R′, CN, halogen, C(═O)H, C(═O)R′, CO₂H, CO₂R′, CH₂OR,substituted or unsubstituted alkyl, substituted or unsubstitutedhaloalkyl, substituted or unsubstituted alkenyl, substituted orunsubstituted alkylidene, substituted or unsubstituted alkynyl,substituted, or unsubstituted aryl, substituted or unsubstituted aralkyland substituted or unsubstituted heteroaromatic; with the proviso thatthe compound is not compound 1, 3 or 4 of U.S. Pat. No. 5,514,708.
 2. Acompound according to claim 1, with the following stereochemistry


3. A compound according to claim 1, wherein R″ is CH₂OH

which may exist as a mixture of the ketone isomer and the hemiketalisomer, or as one of the two isomeric forms.
 4. A compound according toclaim 3, with the following stereochemistry


5. A compound according to claim 4, with the following stereochemistry


6. A compound according to claim 4, with the following stereochemistry


7. A compound according to claim 1 or 2, wherein R″ is a substituted orunsubstituted alkylidene.
 8. A compound according to any of claims 3 to6, wherein at least one of the R substituents is C(═O)R′.
 9. A compoundaccording to claim 8, which is of formula 47


10. A compound according to claim 1, wherein at least one of the Rsubstituents is not hydrogen.
 11. A compound according to claim 10,wherein each group R that is not hydrogen is a protecting group, whichmay be the same or different.
 12. A compound according to claim 11,which is of formula

where R¹, R², R⁶ and R⁷ are hydroxy protecting groups.
 13. A compoundaccording to claim 12, which is of the formula 19:

where R¹, R², R⁶ and R⁷ are hydroxy protecting groups
 14. A compoundaccording to claim 12, which is of the formula 30:

where R¹, R², R⁶ and R⁷ are hydroxy protecting groups.
 15. A compoundaccording to any of claims 12-14, wherein R¹, R², R⁶ and R⁷ are the sameprotecting group.
 16. A compound according to any of claims 12-15,wherein R¹, R², R⁶ and R⁷ are chosen from TBS (tBuMe2Si—), TBDPS(tBuPh₂Si—), TES (Et₃Si—), MOM (CH₃OCH₂—), MEM (CH₃OCH₂CH₂OCH₂—), SEM((CH₃)₃SiCH₂CH₂OCH₂—) and Ac—(CH₃CO—).
 17. A compound according to claim16, wherein R¹, R², R⁶ and R⁷ are chosen from TBS (tBuMe₂Si—) and TBDPS(tBuPh₂Si—).
 18. A compound according to claim 11, which is of formula

where R′ is a hydroxy protecting group.
 19. A compound according toclaim 18, which is of the formula 20:


20. A compound according to claim 11, which is formula 31:


21. A compound according to any of claims 11 to 20, wherein R′ is TBS(tBuMe₂Si—).
 22. A pharmaceutical composition comprising a compound offormula I or a pharmaceutically acceptable salt, derivative, prodrug orstereoisomer or an intermediate of their synthesis thereof, as definedin any of claims 1 to 21, and a pharmaceutically acceptable carrier. 23.The use of a compound of formula I or a pharmaceutically acceptablesalt, derivative, prodrug or stereoisomer thereof, as defined in any ofclaims 1 to 21, in the preparation of a medicament for treating atumour.
 24. A method of treating a tumour which comprises administeringan effective amount of a compound of formula I or a pharmaceuticallyacceptable salt, derivative, prodrug or stereoisomer thereof, as definedin any of claims 1 to
 21. 25. A process for synthesis of a myriaporonecompound of formula 5:

which may exist as a mixture of the ketone isomer and the hemiketalisomer, or as one of the two isomeric forms; wherein the substituentgroups defined by R are each independently selected from the groupconsisting of H, SiR′₃, SOR′, SO₂R′, C(═O)R′, C(═O)OR′, C(═O)NR′,substituted or unsubstituted alkyl, substituted or unsubstitutedalkenyl, substituted or unsubstituted alkynyl, aryl, heteroaryl oraralkyl, and wherein at least one group R is hydrogen; and wherein thegroup R′ is selected from substituted or unsubstituted alkyl,substituted or unsubstituted alkenyl, substituted or unsubstitutedalkynyl, aminoalkyl, aryl, aralkyl and heterocyclic groups; whichcomprises removing a protecting group from an intermediate compound offormula:

wherein the substituent groups defined by R are each independentlyselected from the group consisting of H, SiR′₃, SOR′, SO₂R′, C(═O)R′,C(═O)OR′, C(═O)NR′, substituted or unsubstituted alkyl, substituted orunsubstituted alkenyl, substituted or unsubstituted alkynyl, aryl,heteroaryl or aralkyl, and wherein the or each group R to becomehydrogen in the compound 5 is in the intermediate compound protectinggroup; and wherein the group R′ is as defined.
 26. A process accordingto claim 25, wherein more than one group R in the intermediate compoundis a protecting group.
 27. A process according to claim 25, whichcomprises removing at least one protecting group from a compound offormula 19:

where R¹, R², R⁶ and R⁷ are hydroxy protecting groups.
 28. A processaccording to claim 25, which comprises removing at least one protectinggroup from a compound of formula 30:

where R¹, R², R⁶ and R⁷ are hydroxy protecting groups.
 29. A processaccording to any of claims 25 to 28, wherein R¹, R², R⁶ and R⁷ are thesame protecting group and are removed.
 30. A process according to claim25, which comprises removing a protecting group from a compound offormula 20:

where R¹ is a hydroxy protecting group.
 31. A process according to claim25, which comprises removing a protecting group from a compound offormula 31:

where R¹ is a hydroxy protecting group.
 32. A process for synthesis of amyriaporone compound of formula I:

wherein the substituent groups R and R″ are as defined in claim 1; whichcomprises derivatisation of a compound of formula 5:

which may exist as a mixture of the ketone isomer and the hemiketalisomer, or as one of the two isomeric forms; and wherein the substituentgroups are as defined in claim 25
 33. A process according to any ofclaims 25 to 32, when carried out by the steps of Scheme 1 starting fromcompound 6

where R¹, R², R⁴, R⁶ and R⁷ are hydroxy protecting groups.
 34. A processaccording to any of claims 25 to 32, when carried out by the steps ofScheme 2 starting from compound 6

where R¹, R², R⁴, R⁶ and R⁷ are hydroxy protecting groups.
 35. Acompound of formula

where R¹, R² and R⁴ are hydroxy protecting groups, and L is astereospecific leaving group which induces chirality.
 36. A compoundaccording to claim 35, which is of the formula 10:


37. A compound according to claim 35, which is of the formula 22:


38. A compound of formula

wherein R¹, R², R⁴and R⁶ are hydroxy protecting groups; R⁵ is selectedfrom the group consisting of H, SOR′, SO₂R′, C(═O)R′, C(═O)OR′,C(═O)NR′, substituted or unsubstituted alkyl, substituted orunsubstituted alkenyl, substituted or unsubstituted alkynyl, aryl,heteroaryl or aralkyl; and R′ has the same meaning as defined inclaim
 1. 39. A compound according to claim 38, which is of the formula14:


40. A compound according to claim 38, which is of the formula 26:


41. A process for preparation of a compound of formula 14 whichcomprises chain extension of a compound of formula
 13. 42. A process forpreparation of a compound of formula 26 which comprises chain extensionof a compound of formula
 25. 43. A process for preparation of a compoundof formula 19 which comprises chain extension of a compound of formula18.
 44. A process for preparation of a compound of formula 30 whichcomprises chain extension of a compound of formula
 29. 45. A compound offormula

wherein R¹, R² and R⁴ are hydroxy protecting groups.
 46. A compoundaccording to claim 45, which is of the formula 11:


47. A compound according to claim 45, which is of the formula 23:


48. A compound of formula

wherein R¹, R² and R⁴ are hydroxy protecting groups.
 49. A compoundaccording to claim 48, which is of the formula 8: